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New Synthetic Antibiotics for the Treatment of Enterococcus and Campylobacter Infection Hai-Wei Xu*, Shang-Shang Qin and Hong-Min Liu* New Drug Research & Development Center, School of Pharmaceutical Sciences, Zhengzhou University, No. 100, KeXue DaDao, Zhengzhou 450001, China Abstract: Bacterial resistance to antibiotics, particularly to multiple drug resistant antibiotics, is becoming cause for significant concern. The only really viable course of action is to discover new antibiotics with novel mode of actions. This review focuses on antibiotic resistance mechanisms of Enterococcus and Campylobacter, and new antibacterial agents against Enterococcus and Campylobacter through de novo or semi- synthesis in the period from 2003 until mid- 2013.

Keywords: Antibiotic, Enterococcus, Campylobacter, multiple drug resistant, mechanisms. 1. INTRODUCTION Resistance to multiple antibiotics is spreading throughout the world and the number of reports on therapy failures and rising treatment costs is growing, especially in the hospital environment [1]. More and more bacterial infections evade standard treatment and are difficult if impossible to treat. In many cases, vancomycin is the last option for responsive therapy and determines if a patient lives or dies. However, the advent of vancomycin (glycopeptide) resistance challenges this notion and portends dire public health consequences for the future [2]. All industrialized societies rely on the pharmaceutical industry`s ability to address their inherent medical needs. With infectious diseases, this trust is nourished by the ready supply of a plethora of marketed antibiotics for the immediate treatment of routine or life-threatening bacterial infections. The emergence of resistant pathogens is a rapidly increasing concern to society and has been identified by the World Health Organization (WHO) as one of the three greatest threats to human health[3]. In the US, bacteria are the most common cause of infection-related death. Unfortunately, the pressing need for new classes of antibiotics is still poorly met by the pharmaceutical industry, as illustrated by the recent call by the Infectious Diseases Society of America (IDSA) for a global commitment to develop ten new antibiotics by 2020[4]. Novel, effective, and safe antibiotics are urgently needed [5]. For the reaction mentioned above, many researchers worldwide have been interested in the investigation of rational method to develop novel lead antibacterial compounds [6]. Among them, virtual screening based on QSAR technique has emerged as an interesting alternative to high throughput screening and an important drug-design tool. It *Address correspondence to these authors at the New Drug Research & Development Center, School of Pharmaceutical Sciences, Zhengzhou University, No. 100, KeXue DaDao, Zhengzhou 450001, China; Tel/Fax: 86-371-67781739; E-mails: [email protected] and [email protected] 1873-5294/14 $58.00+.00

has been successfully applied to predict antibacterial drug [7]. Nowadays, multi-tasking QSAR (Mt-QSAR) has emerged. It could describe the biological activity of different drugs tested in the literature against different antimicrobial species [8]. Up to now, Mt-QSAR was only applied to predict antibacterial agent from the previous study and few researches on the discovery of novel antibacterial compounds were reported by this method [9]. However, it is a promising alternative in the field of Computer-Aided Drug Design (CADD), and could rationalize the discovery of compounds with antibacterial activity. This review focuses on antibiotic resistance mechanisms of Enterococcus and Campylobacter, and new antibacterial agents against Enterococcus and Campylobacter by antibiotics through de novo or semi-synthesis in the period from 2003 until mid- 2013. We wish to alert researchers and decision makers to realistically assess society`s urgent medical need for a sustainable supply of effective and safe antibiotics. New ideas and solutions are needed that encourage, facilitate, and support this endeavor. There is no long-term alternative to antibacterial research. 2. ANTIBIOTIC RESISTANCE MECHANISMS OF ENTEROCOCCUS AND CAMPYLOBACTER 2.1. Enterococcus Enterococci: Gram-positive bacteria, are best known as opportunistic pathogens that live in environment and as part of the natural flora in the intestinal tract of animals and humans. Nosocomial infections such as surgical and urinary tract infections and bacteremia caused by Enterococcus, especially E. faecalis and E. faecium present a big challenge for clinicians because of the emergence and rapid spread of multi-drug resistance in these pathogens, which seriously limit clinical therapeutic options [10]. To date, only several antimicrobial agents including daptomycin, linezolid, quinupristin–dalfopristin and tigecycline are available for multidrug resistant Enterococcus infection treatment. Unfortunately, the emergence of E. faecalis and E. faecium resistant to all the agents above but tigecycline was observed world© 2014 Bentham Science Publishers

22 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

wide [11]. Thus, there is urgent need to develop new antibacterial agents for the treatment of infections caused by multidrug and pan-drug resistant Enterococcus. Enterococci are intrinsically resistant to multiple antibiotics and also readily develop additional resistance by mutations and acquiring exogenous resistant genes [12]. The acquisition of resistance genes in Enterococcus often occurs by conjugation and transposition using conjugative plasmids and transposons carrying multiple antibiotic resistance genes [13]. This ability enabled Enterococcus to have the potential for resistance to virtually all clinically useful antibiotics. In order to characterize acquired resistance of Enterococcus, antibiotic resistance mechanisms in E. faecalis and E. faecium were discussed as follows:

Xu et al.

cally unrelated antimicrobial classes including oxazolidinones, phenicols, lincosamides, pleuromutilins, and streptogramin A [19]. The transferable cfr gene was always carried by conjugative plasmids and only two plasmids named pEF01isolated from animal origin and pHOU isolated from clinical harboring cfr gene were described in E. faecalis[17b, 20]. In general, linezolid resistance remains rare in Enterococcus although the emergence of linezolid resistant E. faecalis carrying transferable cfr was observed. Quinupristin–Dalfopristin Resistance: Quinupristin– dalfopristin, a mixture of two semi-synthetic streptogramins B and A, was the first drug approved by the FDA for the treatment of infections caused by VRE. This antibiotic inhibits protein synthesis in Enterococcus by binding to the A2062 site of PTC on the 50S subunit of the bacterial ribosome. To date, there are three mechanisms conferring streptogramin resistance [12-13, 21]: 1) dimethylation of the 23S rRNA target site by the erm genes: 2) drug modification by acetyl action: acetyltransferase encoding genes of vatD, vatE, vatH were responsible for Streptogramin A resistance and vgbA was responsible for Streptogramin B resistance; 3) efflux pump: the ATP-binding cassette (ABC) proteins of MsrC, Lsa and VgaD.

Daptomycin Resistance: Daptomycin, a lipopeptide antibiotic, whose bactericidal activity is mediated by membrane depolarization and permeabilization, is commonly used in the United States and other countries to treat infections caused by vancomycin-resistant Enterococcus (VRE). For daptomycin resistance research [14], comparative study of whole-genome of a daptomycin-susceptible (S613) and a daptomycin-resistant E. faecalis (R712), both of which were isolated from blood of a patient before and after daptomycin therapy, revealed mutations in genes of gdpD and liaF were necessary and sufficient for the development of resistance to daptomycin during the treatment of vancomycin-resistant. The gdpD gene encoding a GdpD-family protein which denotes glycerophosphoryl diester phosphodiesterase, and the liaF gene encoding a protein of a three-component regulatory system (LiaFSR) associated with the stress-sensing response of the cell envelope to antibiotics. The structure of cell envelope and membrane permeability of daptomycinresistant isolate had changed, which reduced the ability of daptomycin to depolarize the cell membrane. In another study [15], three daptomycin-resistant E. faecalis with MICs  256 g/mL were generated in vitro by serial passage through increasing concentrations of daptomycin. Wholegenome sequencing of the three variants indicated the functional link between EF0631 cls mutations and daptomycin resistance. The two reports demonstrated different membrane-associated proteins linked to reduce daptomycin susceptibility in Enterococcus, and also implied that more genes may confer daptomycin resistance, which will be identified in the future.

Campylobacter is one of the most common food-borne pathogens causing bacterial diarrhea in humans. Two thermophilic species including Campylobacter jejuni (C.jejuni) and Campylobacter coli (C.coli) are the main species responsible for most Campylobacter infections [22]. As zoonotic pathogens, these two Campylobacter species are highly prevalent in the intestinal tracts of livestock, especially in poultry, and humans may get infections by consuming contaminated food and milk [23]. In general, the majority of the infections caused by Campylobacter are self-limiting. However, antimicrobial treatments are required for Campylobacter infections cause appendicitis, bacteremia, or other severe complications [24]. For clinical therapy of campylobacteriosis, macrolides and fluoroquinolone (FQ) antimicrobials were commonly used. Unfortunately, the observed fact of a rapid increase in the proportion of FQs and macrolides resistant Campylobacter strains worldwide potentially compromises the efficacy of antimicrobial treatment of human infection[25].

Linezolid Resistance: Linezolid was the first oxazolidinone introduced for clinical use in 2000, and it has an FDA indication for the treatment of VRE infections. It inhibited protein synthesis in bacteria by binding to the A site of the peptidyl-transferase center (PTC) on the 50S subunit of the bacterial ribosome [16]. Mutations in domain V of 23S rRNA are the main mechanism conferring linezolid resistance, of which the G2576T (Escherichia coli numbering) substitution was reported most frequently in linezolid resistant Enterococcus, and other mutations such as T2500A, C2192T, G2447T, A2503G, T2504C, G2505A, G2766T and C2461T were less reported [17]. Additionally, mutations in the ribosomal proteins L3 and L4 were also involved in linezolid resistance [18]. The cfr gene was first identified in Staphylococcus sciuri, encoding an rRNA methyltransferase that modifies A2503 position and inhibits ribose methylation at C2498 in the 23S rRNA, confers resistance to five chemi-

Fluoroquinolones (FQs) Resistance: The point mutations in the quinolone resistance-determining region (QRDR) of DNA gyrase A (GyrA) but not GyrB is mainly responsible for FQs resistance in Campylobacter. The C257T change in the gyrA gene, which leads to the Thr-86-Ile substitution in the gyrase was reported most frequently to confer FQ resistance in Campylobacter [26]. Moreover, this single mutation is sufficient for development of high-level resistance to FQ. Other reported resistance-associated mutations including Asp-90, Ala-70, and Pro-104 were not commonly observed like Thr-86-Ile in FQ resistant Campylobacter [26-27]. In addition to the point mutations in GyrA, the RND-type efflux transporter CmeABC, also plays an important role and confers resistance to FQ resistance by reducing the accumulation of the agents in Campylobacter cells [28]. Normally, CmeABC functions synergistically with the gyrA mutations to confer FQ resistance in Campylobacter.

2.2. Campylobacter

Enterococcus and Campylobacter Infection

The resistance rate of FQs in Campylobacter, especially of strains isolated from animal origin was reported to increase rapidly in recent years. The explanations have been documented that FQs resistance was readily developed, FQresistant mutants could be detected in feces as early as 24 h after the initiation of treatment with FQs, and FQ-resistant clones formed in food animal production can be transmitted to humans through the food chain [29]. In addition, FQ resistant Campylobacter clones could persist stably for long periods in the absence of antimicrobial selection pressure and may outcompete susceptible clones. This reason seriously compromises the efficacy of FQs treatment of human infections [29]. Macrolides Resistance: Macrolides resistance in human isolates is much lower than that reported in food producing animal origin Campylobacter, which made macrolides be the first-choice drug for treatment of Campylobacter infections in human. For macrolides resistance, three mechanisms have been described in pathogenic bacteria including modification of the target sites by mutation or methylation, drug inactivation and active efflux [30]. To date, observations of macrolides resistance in both C. jejuni and C. coli were attributed to mutations in domain V of the 23 S rRNA target gene at positions 2074 and 2075 (corresponding to positions 2058 and 2059 in E. coli) and in ribosomal proteins L4 and L22, and functions of the multi-drug efflux pump CmeABC. However, no rRNA modifying enzymes or macrolide-inactivating enzymes have been described in the two Campylobacter species until now [30-31]. Based on these discovered macrolides resistance mechanisms in C. jejuni and C. coli, explanations on the relative low resistance rate of macrolides comparing with FQs were given by researchers as follows: First, Campylobacter isolates acquired chromosomal mutations in the 23S rRNA gene often imposed fitness burden in antibiotic-free environments and which will decrease in number when compete with macrolide-susceptible Campylobacter [32]. Second, the mutation frequency for macrolide resistance in Campylobacter is much lower than that of FQ resistance (approximately 10,000-fold) [29]. Third, the process of macrolide resistance development is slow, and often needs several weeks of exposure to macrolide antimicrobials [32]. These findings above strongly recommended macrolides as the first choice for clinical therapy of campylobacteriosis. 3. NEW ANTIBACTERIAL AGENTS AGAINST ENTEROCOCCUS 3.1. -Lactam Antibiotics The -lactam group of antibiotics is the first class of antibacterial natural products introduced as a therapeutic treatment of bacterial infections. -Lactam antibiotics inhibit bacterial growth by interacting with PBPs enzymes that are normally involved in the terminal transpeptidation (crosslinking) steps of bacterial cell-wall biosynthesis. Owing to their broad antibacterial spectrum, their clinical efficacy, and their excellent safety profile, research of -lactam antibiotics has been one of the preeminent areas of pharmaceutical drug discovery. However, -Lactam antibiotics are not the most effective agents for Enterococcus infection treatment. The first clinical carbapenem, imipenem (1), and the first clinical

Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

23

carbapenem with a -methyl group in position 1, meropenem(2), show moderate antibacterial activity with MICs of 1.56M/ml and 12.5M/ml[33]. A few reports focus on the research of new antibiotic against Enterococcus by the structure modification with -Lactam as a lead. NH

OH H

OH H

HN S

N O

H N

O NMe2

S

N O

COOH

COOH

meropenem 2

Imipenem 1

In contrast to other -lactams, carbapenems are stable to most clinically relevant -lactamases, which inactivate the antibiotics by hydrolyzing the -lactam ring. 1--methyl substitution rendered carbapenems stable to hydrolytic degradation by renal dehydropeptidase I, a discovery that was immediately taken up and explored through related structural variations. Most structural exploration efforts focused on modification of the at the C-2 position in the carbapenem skeleton with different groups, such as a spiro[2,4]heptane moieties(3), a 5`-piperidinylmethyl or a pyrrolidinylmethyl3`-ylthio moiety (4), a 5`-(1,2-disubstituted ethyl)pyrrolidin3`-ylthio group (5), 5`-piperidine(6) and pyrrolidine derivatives substituted pyrrolidin-3`- ylthio group(7). The in-vitro antibacterial activities of the new carbapenems (2-7) prepared above against E. faecalis are listed in Table 1[33]. For comparison, the MIC values of imipenem and meropenem are also listed. All compounds displayed superior antibacterial activity against E. faecalis to meropenem (2), but similar or worse antibacterial activity to imipenem (1). H N

OH H

O N

N O

OH

H N

OH H

S

N N

O

COOH

COOH

Carpenem 4

Carpenem 3

H N

OH H N O

OH COOEt

Carpenem 5

H N

N N

S COOH Carpenem 7

S COOH Carpenem 6

O OH COOEt

O N

N O

COOH

O

H N

OH H

S

OH H

NOH

S

COOEt OH

24 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

Xu et al.

In Vitro Antibacterial Activity of the Carbapenem Derivatives Against Enterococcus Faecalis 2347.

Table 1.

Comps. Strains

MIC(g/ml) a

3

4

5

6

7

MPM(2)a

IPM(1) b

3.125

1.563

3.125

6.25

6.25

12.5

1.56

Meropenem. bImipenem.

3.2. Macrolide and Ketolide Antibiotics Macrolide antibiotics, a subgroup of the polyketide natural products, are an important class of therapeutic agents that act against community-acquired respiratory infections such as community-acquired pneumonia (CAP), acute bacterial exacerbations of chronic bronchitis, acute sinusitis, otitis media, and tonsillitis/pharyngitis [34]. Macrolide antibiotics block bacterial protein biosynthesis by binding to the 23S ribosomal RNA of the 50S subunit and interfere with the elongation of nascent peptide chains during translation [35]. Enterococcus is not their predominant pathogen. Despite their bacteriostatic mode of action, there is research on the antibacterial activity of macrolides against Enterococcus. Clarithromycin (8) is a second-generation macrolide antibiotic which shows good antibacterial activity against E. faecalis with MIC of 0.78-0.56 g ml–1. Telithromycin (9), the first ketolide antibiotic, whose activity is 7-30 fold more that of than Clarithromycin (8) against E.faecalis [36] (Table 2). Systematic SAR exploration of the ketolide backbone unveiled various novel ketolide series with potent activity. A C11/12 cyclic carbamate group enhanced the activity against susceptible and resistant strains by stabilizing the ketolide conformation, and the hetero-aryl groups are responsible for improved activity against erm methylase mediated resistance owing to additional interaction and enhanced affinity for methylated ribosomes. Structural modifications of the crucial heterocyclic moiety were systematically investigated and telithromycin (9) emerged as the leading compounds. O

N OMe

O O

N HO

HO O

O O

O

OMe

OH

OMe

NMe2

O Clarithromycin (8)

HO O

O

O O

OMe

O

OMe

N NMe2 O

O

OH

evaluated against E. faecalis, and appeared as the most active compound identified within the derivatives of (-)-A26771B. Both compounds have improved antibacterial activity and metabolic stability than (-)-A26771B [38] (Table 3). N

Cl N

O

N

O

N

O O

O

O

N

O

O

N

O O

HO O

O

OMe

NMe2 O O

Ketolide (12)

NMe2 O

O

Ketolide (13)

H N

O

O

O O

HO O

O

O

O

OMe

N O

OMe

O

O

N

OMe

O

O

NMe2 O

Ketolide (11)

N

O

HO O

O

O

O

N N

OMe

NMe2

Ketolide (10)

Cl

OMe

N O

OMe HO O

O

OH

OMe

O 15 and 16 sepaarated by flash chromatography

(-)-A26771B (14)

3.3. Lincosamides Lincosamides exert their antibacterial activity by binding to the ribosome and inhibiting bacterial protein synthesis. Of the lincosamide class of antibacterial protein synthesis inhibitors, clindamycin (17) is the most widely used in human medicine. These low molecular-weight antibacterial agents exhibit a spectrum similar to that of the macrolides, including activity against most Gram positive organisms and the anaerobes, but not the Gram negatives. O

Natural product (-)-A26771B (14) is a 16 member ring macrolactone possessing a highly oxidized -oxo--hydroxya ,-unsaturated carboxyl system. (-)-A26771B exhibits moderate in vitro activity against Gram-positive bacteria including E. faecalis. Macrolactams 15 and 16 were then

N

N O

telithromycin (9)

Novel C12 vinyl ketolides 10 and 11 showed a comparable activity against Enterococcus to the commercial ketolide telithromycin(9). Similarly, the C12 ethyl ketolides 12 and 13 showed a comparable antimicrobial activity to the commercial ketolide telithromycin(9) [37].

N OMe

N

Cl O N H HO

O

OH OH

Clindamycin (17)

Cl

SMe NH

N H HO

O

SMe OH

OH Lincosamides (18)

Clindamycin (17) show moderate antibacterial activity against Enterococcus with MICs of 0.125-8g/ml (Previous study suggested that clindamycin exhibit no activity) [5, 39]. Azetidine lincosamides (18) with an alkyl side-chain on the ring is a semi-synthetic derivative of Clindamycin, which

Enterococcus and Campylobacter Infection

Table 2.

Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

25

In Vitro Antibacterial Activity(MIC, g ml–1) of the Ketolide Derivatives. Comps. Strains

a

10

11

12

13

8a

9b

E. faecalis 29212

0.1

0.05

0.05

0.05

O.78-1.56

0.05-0.1

E. faecalis bc11148-2

0.78

0.1

1.56

25

50

0.4

b

Clarithromycin. Telithromycin.

Table 3.

In Vitro Antibacterial Activity (MIC, g ml–1) of (-)-A26771B and its Analogs. Comps. Strains 14

15

16

E. faecalis ATCC 29212

16

2

2

E. faecalis 1

4

0.5

0.5

shows 10 fold more active than that of clindamycin (17) against E. faecalis [39]. 3.4. Glycopeptide Antibiotics Glycopeptide Antibiotics have a linear heptapeptide backbone (configuration R, R, S, R, R, S, S), in which some aromatic amino acid residues are cross-linked (biphenyl and diphenylether motives) to build a rigid concave shape. Glycopeptide antibiotics inhibit bacterial cell-wall biosynthesis by recognizing and strongly binding to the L-Lys-D- Ala-DAla termini of peptidoglycan precursor strands at the external side of the membrane. In this way, transpeptidases are prevented from executing their cross-linking job [40]. Owing to the lack of cross-resistance to other antibacterial drugs, the glycopeptide antibiotics have become first-line drugs for the (parenteral) treatment of life-threatening multi-drug resistant infections by Gram-positive bacteria in many hospitals [5]. Vancomycin (19) is the first glycopeptide antibiotic introduced into clinical practice. It is the antibiotic of last resort used to treat Gram-positive bacterial infections, especially those caused by methicillin-resistant Staphylococcus aureus and for patients allergic to -lactam antibiotics. With the rise of MRSA infections in hospitals, vancomycin (19) became the antibiotic of last resort, but owing to its frequent use, resistant Gram-positive pathogens, in particular VRE have emerged and worryingly spread. In the main resistance phenotypes (VanA and VanB), the molecular recognition site D-Ala-D-Ala (X=NH) of the peptidoglycan precursor strands is replaced by a D-Ala-D-lactate terminus (X=O) [41]. (Fig. 1) This “simple” replacement of amide by ester at the peptidoglycan terminus, that is, the loss of a single hydrogen bond (C1.4-carbonyl to X=O) and concomitant creation of a destabilizing lone pair/lone pair interaction between the ligand and antibiotic notably results in a 1000-fold decrease in binding affinity and a dramatic loss in antibacterial activity[42]. Boger and co-workers have selectively omitted the “disturbing” C1.4-carbonyl functionality. Their synthetic C1.4deoxo congener of vancomycin (23-24) exhibited enhanced affinity for the D-Ala-D-lactate terminus (no repulsive interaction), leading to restored antibacterial activity against re-

sistant pathogens including resistant VanA bacteria(Table 4) [43]. A modified peptide ligand possessing a methylene in place of the lactate oxygen restores 100-fold of this binding affinity by removal of a destabilizing lone-pair interaction. This suggested that removal of the residue 4 carbonyl in the vancomycin aglycon would produce an analogue with enhanced affinity for D-Ala-D-Lac and might restore much of the biological activity of the molecule that is lost with resistant bacteria. OH

NH2

OH OH

O CH2OH O O

O

R= vancomycin(19) R = H vancomycin aglycon(20) OR

O C O

HO 6

O

H

NH 7

H3CO2C HO

5

N H H H

Cl H N

O D 4 O

O

3

H NH

E H N

OH 2 NH O

H2NOC

B A

N H NHAc

1 O NHMe

OH OH O

O AcHN

Cl

X

O

O

N,N`- Ac2-L-Lys-D-Ala-D-Ala, X=NH (21) N,N`-Ac2-L-Lys-D-Ala-D-Lac, X=O(22) Fig. (1). Schematic representation of the interactions between vancomycin (19), vancomycin aglycon (20), and model ligands N,N’Ac2-L-Lys-D-Ala-D-Ala (21) and N,N’-Ac2-L-Lys-D-Ala-D-Lac (22).

The resulting methylene derivative vancomycin aglycon (23) exhibits significant activity against resistant VanA bacteria. Unnatural amino acid in compound 23 presents an Hbond donating group. The H-bond to the residue 2 carbonyl of the ligand might further enhance its affinity for the model

26 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

Table 4.

Xu et al.

Binding and Antimicrobial Properties of 19-24.

Ka (M-1)

VanA,c MIC (g/mL)d

Comps.

19, vancomycin

a d

21a

22b

2.0 x 105

1.8 x 102

1100

>500

5

2

1400

>500

Ka21/Ka22

20, vancomycin aglycon

1.7 x10

23

4.8 x 103

5.2 x 103

0.92

31

24

3

3

0.40

31

1.6 x 10

b

1.2 x 10

4.1 x 10

c

Ac2-L-Lys-D-Ala-D-Ala. Ac2-L-Lys-D-Ala-D-Lac. Enterococcus faecalis (VanA, BM4166). Vancomycin and vancomycin aglycon exhibit MICs of 1-2.5 g/mL against wild-type E. faecalis. OH O HO O O NH

Cl H N

N H H H

OMe OH

O

H N

H N H H2N

O Cl CO2Me

HO

O NHMe

O

N H

O

H HO2C HO

Cl O O O NH

N H H H

Novel resistance-breaking glycopeptides possess structural elements that promote dimerization and membrane anchoring. Dimerization causes tighter binding of ligands terminating in D-Ala-D-lactate, whereas lipophilic side chains endorse anchoring in the cytoplasmic membrane, thereby helping to position the antibiotic close to its target and eventually disturb the bacterial-membrane integrity. These effects have stimulated chemists to prepare covalent vancomycin dimers. Lipophilic side chains can restore activity against VRE. Boger and co-workers[45] have designed and synthesized an array of 40 covalently vancomycin dimers linked through the carboxyl terminus (C), the amino terminus (N), the vancosamine amino group (V), and the resorcinol side chain of amino acid residue 7 (R). The box presents a simplified depiction of vancomycin where the heptapeptide core is abbreviated as a diamond shape but with the functional groups at C-, N-, V- and R-positions explicated (Fig. 2). Both linkage orientation and linker length influence the in vitro activity of vancomycin dimers. With respect to linkage orientation, the V-V series displayed the greatest potency against vancomycin-susceptible organisms and Van B VRE, and the C-C, C-V, and V-R series displayed the most promising broad spectrum of activities that included VanA VRE, while the N-N linked series was the least potent against the test Organisms. Most of the dimers were more potent than vancomycin against EFSVS, EFSVB, and EFMVA. Dimers

H N

N H H

O NHMe

N H

O NC

OMe OMe

23

ligand 21 or 22, and thereby further improves the antimicrobial property. The premise was first investigated by preparing vancomycin aglycon Analogues that bear modifications in the N-Terminal D-Leucyl Amino Acid. However, their antimicrobial properties of them against VRE (VanA), did not display markedly difference than the natural product [44].

OH

O

H MEMO MeO

OH OH

N

Cl O

24

bearing shorter linkers are in all cases the most potent against the VRE strains (EFSVB, EFMVA, EFSVA), but dimers joined by short linkers are preferred in only 12 of the 50 cases involving EFSVS or non-Enterococcus. This indicates that penetration of the cell wall to the sites at which glycopeptides exert antibacterial effects is hindered in VRE relative to vancomycin-susceptible organisms. However, significant changes in cell wall structure in vancomycinresistant versus vancomycin-susceptible Enterococcus have not been reported, and the dimers joined by the shortest linkers showed the most potent activity against EFSVS. in only 2 out of 10 cases (i.e., with the C-N and N-N linkage series). NH2 V O C HO

HO

OH

OH HO

NH N R

NH

O

O

Cl H N

O O

N H H H

NH2

V Cl

O HO

H N

NH2

O

O O

H

O

OH

O NH H NH O

NH O

H2NOC

O

N

NH2

H

N H2N

N H

O

C HO2C HO

NH N R

N H

OH OH O

O N H

HN O NH2

N H

NH O

O

Van Susceptible

O

Van Resistant

O O

O

Fig. (2). Structure of vancomycin (19) complexed to terminal DAla-DAla and D-Ala-D-Lac segments of ligands displayed by vancomycin susceptible and –resistant bacteria, respectively. Hydrogen bonds are indicated as dotted lines.

Hydrophobic derivatives of vancomycin aglycon (e.g., 25-26) exhibited equipotent antimicrobial activity against the sensitive and VanB resistant bacteria and displayed im-

Enterococcus and Campylobacter Infection

Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

proved activity against VanA bacteria without possessing significantly altered binding affinity formodel ligands 21 and 22 [41]. This profile of activity is identical, but less potent than that of chlorobiphenyl vancomycin(oritavancin (27)) and teicoplanin (28), which bear hydrophobic side chains on the saccharides attached to the phenol of the central residue (Table 5). Impressively, analogous methyl ether derivatization of the teicoplanin or ristocetin aglycons similarly provided equipotent antimicrobial activity against sensitive and VanB resistant bacteria, establishing the generality of the observations. Notably, derivatives such as 25-26 lack a lipid side chain and a disaccharide, suggesting that membrane anchoring and transglycosylation inhibition effects invoked for teicoplanin and 27 may not account for the origin of the effects with 25. OR1 O Cl

HO O O NH

N H H H

H N

Table 6. OH

O

H N

N H H O H2NOC

O

N H

O

NHMe

In Vitro Antibacterial Activity(MIC, g ml–1) of 2730. MIC, (g/mL) Strains 27

29

30

Enterocouccus spp. VanB

1

1

2

Enterocouccus spp. VanA

4

128

8

OR2 OR3 1

2

3

4

5

Comps

R

R

R

R

R

25

Me

Me

Me

Me

H

26

Me

Me

Me

Me

Me

Table 5.

moieties (two D-mannoses, D-glucose, D-arabinose, Lrhamnose and L-ristosamine) attached to the aglycon. In spite of its good antibacterial activity against Gram-positive strains, this antibiotic has not been used in therapy, due to its unwanted side-effect to cause aggregation of blood platelets [46] . Since lipophilic N-alkyl derivatives of glycopeptide antibiotics show considerable activity against vancomycinresistant bacteria, the concept of inserting lipophilic substituents led to several active antibiotics and the subclass of lipoglycopeptides (e.g. Oritavancin(27), dalbavancin(29) and telavancin(30)). Isoindole and benzoisoindole derivatives of ristocetin aglycon (32-37) have been prepared by the reaction of o-phthalaldehyde or naphthalene-2, 3-dialdehyde with various thiols. The new compounds exhibited potent antibacterial against E. faecalis containing Van B and Van A [46] (Table 7).

Cl O

H R5O2C R4O

27

In vitro Antibacterial Activity(MIC, g ml–1) of 2528.

MIC, (g/mL) Comps. E.faecalis VanB

E.faecalis VanA

Vancomycin(19)

>100

>100

Vancomycin anlycon (20)

>100

>100

25

2.5

80

26

1.6

40

27

0.03

10

Teicoplanin(28)

0.2

>100

Oritavancin (LY-333328, 27), dalbavancin (BI-397, 29), and telavancin (TD-6424, 30) are three semi-synthetic second-generation drugs [5]. Oritavancin (27) is the 4’chlorobiphenylmethyl derivative of the natural vancomycin analogue chloroeremomycin. Dalbavancin (29) has a similar antibacterial activity but is not active against VRE of the VanA resistance genotype (Table 6). Telavancin (30), the youngest and most promising congener, encapsulates the essential aspects of a successful glycopeptide optimization: in search of glycopeptides with improved in vitro activity. Ristocetin A (31) is a glycopeptide-type antibiotic produced by Nocardia lurida. This molecule contains six sugar

Through chemical post evolution, the new, semisynthetic glycopeptide antibiotics have achieved significant technical progress over their established natural congeners in terms of activity against resistant strains and pharmacokinetic and pharmacodynamic properties. It will be interesting to learn to what extend these favorable profiles will be reflected in cure rates during advanced clinical trials. If approved, these compounds could become valuable drugs for the treatment of severe infections with multi-drug resistant pathogens. 3.5. Cyclic Peptide and Depsipeptides Antibiotics Cyclic peptides and depsipeptides are a class of privileged molecular structures. In comparison to linear peptides, cyclic peptides are more stable against proteolytic degradation due to their lack of free N- or C-terminus and reduced conformational freedom [47]. In addition, cyclic peptides are more bioavailable than linear peptides due to the absence of N- and C-terminal charges and their ability to form intramolecular hydrogen bonds as they traverse the lipid bilayer. For example, In September 2003, daptomycin (Cubicin; Cubist Pharmaceuticals), the first member of cyclic peptides was approved by the US FDA for the treatment of infections caused by Gram-positive bacteria [48]. Given their potential as drugs, drug leads, and molecular tools in biomedical research, there has been much interest in the generation of cyclic peptide and depsipeptides natural product analogues. Gramicidin S (GS, 38) is an amphiphilic cyclic decapeptide bearing the C2-symmetrical sequence cyclo (Pro-ValOrn-Leu-DPhe)2. It acts as an antibiotic by targeting the membrane lipid bilayer. Gramicidin S (GS, 38) analogues 39-41 contain arylated sugar amino acids (SAAs) as a replacement of one of the two DPhe-Pro -turn regions.

28 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

Xu et al.

Cl HO

HN

OH OH

O

CH2OH O

O Cl

HO O O NH

H N

N H H H

O

Cl O

O OH

O

H N

N H H O H2NOC

O

O

NH

NHMe

N H

HN O O Cl O

O Cl

O O

O

OH CH2OH

O

H N

N H H H

OH

O

HO2C HO

OH

O O

H0 O OH O

HO CH2OH OH

27

H N

28 HO O

HO O

NH

NMe2

O NHMe

N H

O

O NH

H

N H H H

O OH O

HO

HOOC

HO

O

N H H

O CONH2

OH O

OH

O

HO

OH

O

O

HO

OH OH

O

CH3

O

OH

HO O

O

O

O

CH3 OH O

O

O O H H O N N N H H H H O NH

OH

O

O

H N

O

O OH OH

HO

O

H

O

H0

H3COOC HO

OH

CH3

OH

HO

HO

32-37

31

32 N

R

NR

N H

OH OH

Comps

CH3

O

H N

H

H

O

H0

HOOC

OH

O O H H O N N N H H HH O NH

NH2

N H

O

O

HO

H

HO

NHMe

N H

30

HO HO

O

H N

O P OH OH

HN 29

33 OH

34

35

N

N

36

N

37 N

N

OH

S O

S

S OH

S

S

N

N

S

S

N

OH

Table 7.

OH O

H N

OH OH

HO

CH2OH OH

OH OH

H2N

O

H O

H0

HNOC

HO

Cl

O Cl

O

H N

N H HCl O

OH CH2OH

O

O

HO

O

OH O

O

H N

N H H H

O OH COOH

O Cl

O Cl

HN

OH

N H O

NH2

N H

OH OH

OH

O

O

H N

N H H

H

H HO2C HO

O

CH2OH

HN O

(CH2)6CH2(CH3)2

OH OH

O

N N

Antibacterial Activity of Reference and Newly Synthesized Ristocetin A Derivatives.

MIC, (g/mL) Bacterium strains 19

28

31

32

33

34

35

36

37

E. faecalis ATCC 29212

1

1

4

1

2

0.5

0.5

0.5

2

E. faecalis ATCC 15376 van A

256

256

16

1

4

1

0.5

0.5

2

E. faecalis ATCC 51299 van B

128

0.5

256

2

1

2

0.5

0.5

2

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Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

29

NHR NH2 O N H

N

O

O

H N

H N

N H

O

N H

N

O

O

O

H N

N H

N H

O

H N

N H

O

O

OR`

O O

N

H N

O

O O

O

H N

O

H N

N H

H N

N H

O

OH O

O RHN

H2N 39

38 R,R`=

GS analogues 39-41 proved to be as active as the parent GS itself as antibacterial agents against E. faecalis with MICs of 8-32g/ml and are equally efficient in lysing red blood cells [49]. Tyrocidine A (42) is a cyclic decapeptide antibiotic produced by Bacillus brevis. It adopts a -pleated sheet conformation under physiological conditions. It is believed that tyrocidine A and other cationic peptides kill bacteria by disrupting their cell membranes [50]. As such, it is difficult for bacteria to develop resistance to this type of antibiotic because it would require significant alteration of the membrane structure. However, clinic application of tyrocidine A is limited by its low selectivity toward microorganism, such as it also disrupts mammalian cell membranes, as indicated by its high hemolytic activity [51]. OH

NH2 O

H N

O 10

O

HN

8

9 N H

H 7 N O

N

O 2 N H

H N

O

O O

4

3 O

O NH2

HN 5

1 O

NH 6 O

N H

NH2

42

Substitution derivatives of Tyrocidine A at position 4, 6, 7, 10 were synthesized [51-52], which have significantly improved therapeutic indices compared to the natural product. Previous studies have shown that substitution at position 4 (D-Phe) or 6 (Gln) resulted in large changes in both antibacterial and hemolytic activities. Positions 7 and 8 appeared to be more tolerant to mutations, while ornithine (Orna) at position 9 was found to be important for antibacterial activity, likely because it provides the positive charge to the peptides. 3.6. Thiazolyl Peptide Antibiotics Thiazolyl peptide antibiotics are highly modified cysteine-containing macrocyclic peptides with several distinctive common features: the presence of thiazole rings, unusual amino acids, dehydro amino acids, and a highly substituted pyridine centerpiece. [53] They display potent antibacterial activities against a variety of Gram-positive bacteria, includ-

41

40 ,

,

,

ing multiple drug resistant strains E. faecium (MREF), vancomycin-resistant E. faecium (VREF). Thiazolyl peptide antibiotics disrupt bacterial protein biosynthesis by interacting directly with the 23S rRNA region of the ribosomal protein L11 [53]. Even though these antibiotics have been known for nearly half-a century, so far no thiazolyl peptide has entered clinical study for human use, presumably due to the poor in vivo activity [54]. Thus, the modification of thiazolyl peptide antibiotics focus on the on an investigation to modify the nocathiacins to improve their aqueous solubility while maintaining their intrinsic biological activity. One of the most prominent member is thiostrepton I (43), and some analogues(44-55) containing both acidic and basic polar groups have retained good in vitro activity and in vivo potency of the parent Table 8 [53, 55]. Thiazomycin (57) is a new thiazolyl peptides derivative, which was discovered by congener mining using chemical screening methods of LCHRMS. Continued mining led to the discovery of a new congener thiazomycin A (58), an equally potent antibacterial agent, from Amycolatopsis fastidiosa. They have specific inhibition of protein synthesis and a potent Gram-positive antibacterial agent including Enterococcus. with minimum inhibitory concentration (MIC) ranging 0.002–0.25 g/mL[56]. Philipimycin (59), a thiazolyl peptide was isolated from a soil sample collected in Namaqualand, South Africa. Philipimycin (59) exhibited very good activity (MIC, 0.03g/mL) against vancomycin, linezolid, and macrolide resistant E. faecium. The truncated compound 60 was less active across the board and exhibited MIC values of 0.5 g/mL aginst E. faecalis) and 0.12 g/mL against E. faecium[54]. 3.7. Tetracycline Antibiotics Tetracyclines are a unique chemical class of antibiotics that act to inhibit protein synthesis at the level of the bacterial ribosome. However, decades of widespread tetracycline use has resulted in significant bacterial resistance and has drastically decreased these agents’ efficacy against a wide range of organisms [57]. Two main mechanisms of tetracycline resistance have been reported to date: (1) active drug efflux (tet(A)tet (D), and tet(K)tet(L)), widely found in both Gram-positive and Gram-negative pathogens and (2) ribosomal protection (e.g., tet(M)tet(O)), more commonly seen in Gram-positive organisms [58].

30 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

Table 8.

Xu et al.

Antibacterial Activity of Reference and Newly Synthesized Thiostrepton I Derivatives.

MIC(g/mL) Bacterium strains 43

44

45

46

47

48

49

50

51

52

53

54

55

56

E. Faecalis A20688 (MSEF)

0.03

0.06

0.015

0.03

0.003

--

--

0.03

0.03

0.03

0.07

0.03

--

--

E. Faecalis

0.03

--

--

--

--

0.03

0.015

--

--

--

--

--

--

--

E. Faecalis C21560

0.03

--

--

--

--

--

--

--

--

--

--

--

0.016

0.03

OH

S N

S

OH

O

H N

S

NH

S O

NH HO O NH

O

NH

O S

O O

H O

NH

O

O

HO

43

O

S

N

N S

O

N

S

S

O NH

N NH O

46

48 49

2

R

R

Comps.

50

H

1

NR R

HN

H

Comps.

52

CH2P(O)(OEt) 2

H

NR1R2

HN

CH3

CH3

OC

47

N

1

OC

N

N H

O

O

HO N

Comps

OH N

O

H O

O

O

HO

R2

O

O

H O

R1

O

N

S

N

O

NH O

O NH

O

N O

S O

HO OR1 N

O

N

O

NH O

O

H N

N

NH

NH

O

S

N S O

S N

NH2

N

N O HO

OH

O

N

NH

45

O

H N

O

O

HO

44

OR2

O

H O

N

N

S

O

O

HO

O NH

O

H O

OH N

N

N

S

O

NH O

O

O

O

O

NH

O

N

N

S

N

O

HO OH N

NH2 O

S O

NH

O

N

S

N NH

NH O

O

OH N

N

S S

HO

O

NH O

O

H N

N

O

HO

S O

S N

S

N

N N

O

N

OH

NH2 O

N N

N O

O

H N

N

NH2 O

N

S

OH

N N

Structure activity relationships (SAR) and the solved tetracycline 30S ribosome co-crystal structure [59] indicate that the “southeast” portion of the molecule is directly involved in interactions (mainly H-bonding) with the bacterial ribosome and should be largely conserved in order to retain high levels of ribosomal binding. In contrast, the “northwest” portion of the molecule does not directly interact with the ribosome and can be modified without substantial loss of activity. Structural variations in the D-ring region of tetracyclines

2

 51 OH

HN

O P OMe OMe

53 HN OH

OH

have emerged as one of the most promising approaches for improved potency and pharmacological properties as shown by previous generations of tetracyclines such as tigecycline (61), which is highly potent and capable of overcoming tetracycline resistance[57]. Pentacycline (62) [60] is a novel tetracycline analog by total synthesis with promising antibacterial activity against both Gram-positive and Gram-negative organisms. These

Enterococcus and Campylobacter Infection

Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1 OH

R1 N

S N

OH

S

H N

N S

NH

NH

O

OH N

N

S

N NH

O

O

H O

O

Comps

55

O

N

O

HO N

N

54

analogs were based on a “pentacycline” scaffold, which has an additional benzene ring (E-ring) fused in a linear fashion to the C8 and C9 carbons on the tetracycline D-ring. Recently, X Y Xiao et al. [61] synthesized some novel pentacyclin analogs with systematic variations at C7, C8, C9, and C10 and they were evaluated for antibacterial activity. Several analogs (63-65) have similar or comparable antibacterial activity against E. faecalis including tetracycline resistant strains. Although all pentacycline analogs prepared so far are less potent in vitro than tigecycline (61), a number of analogs showed in vivo efficacy comparable to tigecycline when dosed intravenously in a mouse septicemia model. Several analogs had promising oral bioavailability in rats and cynomolgus monkeys, while tigecycline had almost no oral bioavailability in rats. Moreover, compound 65, a 10-(3fluoroazetidino) methyl pentacycline analog, showed promising in vivo efficacy comparable to tetracycline when dosed orally in the mouse septicemia model.

N H

NR1R2

N

OH

HO

N

HO

NH O

O NH

O

N

O

S

O NH RO

O NH O S

MeO

59 R =

O

O O OMe OMe

60 R =

R2

R3

O HN

NH2

O

OH O N

O

58

HN

NH2

O

O O OH

O

OH O N

OH OMe

O OMe

57

O O

R3O

R1

NH

O

R2

O

Comps

S

N

NH HO

O NH

NH2

N

NH

N

O

O

N

N

S S

S

S O

NH

O

O O

N

H N

N

O

N

O

S N

S

S

N

O

Fluorocyclines are a new generation of tetracycline antibacterial agents, accessible through a recently developed total synthesis approach. Fluorocyclines possess potent, broad spectrum antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. A large variety of amines on the C9 side chain were systematically explored. Compound 66, with a pyrrolidine on the C9 side chain, was the most potent analogue in this fluorocycline series, having MICs  1 g/mL against Gramnegative bacteria including those express the Tet(A) efflux protein. Compared to tigecycline, compound 66 was 4- to 16-fold more potent against S. aureus, E. faecalis, E. Coli EC107, and A. baumannii AB110 and was equipotent to tigecycline against all other strains in the panel [61].

R1 S

N

N H

O

N

OH

56

O

H O

O

HO

OH N

O

O NH

O

N

S S

N

O

NH O

O O

NH O

O

S

HO

S O

NH

N S O

NH

N

O HO O

N O

SO2CH2CH2NEt2

R2

O

N

NH2 O

N N

S

O

31

OH OMe

Compound 66 also displayed potent ribosomal inhibition, promising in vivo efficacy in animal infection models and desirable pharmacokinetic properties in rats. Compound 66 was selected for further preclinical studies and demonstrated favorable pharmacological and toxicological profiles. Following IND filing, compound 66 has successfully completed phase 1 single- and multiple-ascending dose studies in man. Currently, compound 66 is being evaluated for treatment of adult community-acquired intra-abdominal infections in a global phase 2 trial. [61]

32 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

Xu et al.

64 R =(CH3)2NCH2 65 R = 3-F-azetidinometyl

3.8. Quinolone Antibiotic Quinolone antibacterial agents are among the most attractive drugs in the anti-infective chemotherapy field. These antibiotics exert their effect by inhibition of two type II bacterial topoisomerase enzymes, DNA gyrase and Topoisomerase IV. The structure–activity relationship (SAR) study of quinolone antibacterial agents showed that the N-1, C-7, and C8 substituents play an important role in the antibacterial potency, antibacterial spectrum, and toxicity of fluoroquinolones [62]. In general, the optimal substituents at the C-7 position have proven to be 5- and 6-membered nitrogen heterocycles that contain peripheral nitrogens [63]. The majority of quinolone C-7 substituents can be arranged into three main categories: the piperazinyl, pyrrolidinyl, and piperidinyl type side chains [64]. The presence of a carboxylic acid group at the 3- position of the fluoroquinolone scaffold is essential for antibacterial activity.

at the C-10 position were synthesized. They exhibited superior in vitro antibacterial activity to 67 against quinoloneresistant clinical isolates and VREs [62]. As the candidate compound, the in vitro and in vivo antibacterial activities of 71 were carried out for further evaluation. Compound 71 showed 4- to 9-fold smaller IC50 values against both the wild-type DNA gyrase and topoisomerase IV, and over 40fold smaller IC50 values against both the resistant type DNA gyrase and topoisomerase IV compared with levofloxacin, which has the same pyridobenzoxazine nucleus as 71. Further investigations of 71 for clinical trial are in progress [62]. NH2 O

NH2 O F

F

COOH

N

N H2N

O

H 2N

H

69

NH2 O F

NH2 O COOH

F

N

NH2 O F

COOH

N H2N

N CH3

F

F H 67

Using 67 as lead, novel pyrido [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid derivatives 68-71 carrying a 3cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety

O F H

68

Despite a large number of fluoroquinolones approved for the treatment of bacterial infection, there have been unabated efforts for the discovery of new quinolones with specific properties and most importantly to overcome the problem of growing bacterial resistance. 10-(3-cyclopropylamionomethyl-1-pyrrolidinyl)pyrido [1, 2, 3-de] [1,4] benzoxazine derivatives (67, DQ-113) exhibited comparable or greater antibacterial activities than the other quinolones tested such as vancomycin, teicoplanin, quinupristin/dalfopristin, and linezolid against clinically isolated resistant Gram-positive bacteria. 67 showed favorable profiles in preliminary toxicological and nonclinical pharmcokinetic studies, which was selected for further preclinical evaluation [65].

COOH

H2N

COOH

N O

H H 70

F

H 2N

O

F

F H 71

The fluoroquinolones 72-76 are novel fluoroquinolones containing substituted piperidines. Their antibacterial activities against methicillin-sensitive S. aureus (MSSA), S. pneumoniae, and E. faecalis (MICs < 0.001 g/mL) were four times more potent than those of gemifloxacin and vancomycin, and 100 times superior to that of Linezolid[63]. Compound 77 is a 4, 5, 6, 7-tetrahydro-thieno [3, 2-c] pyridine quinolones, which exhibited antibacterial activity against the resistant strains such as methicillin resistant S. aureus, vancomycin resistant E. faecalis. It shows superior antibacterial activity than gatifloxacin, ciprofloxacin, and sparfloxacin. 3-aminoquinazolinediones as a novel class of bacterial gyrase and topoisomerase IV inhibitors demonstrate outstanding in vivo efficacy, particularly against Gram-positive organisms, in murine infection models. The SAR around the

Enterococcus and Campylobacter Infection

Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

quinazolinedione core was explored and the optimal substitutions were combined to give two compounds, 78 and 79, with exceptional enzyme potency (IC50 = 0.2 M) and activity against Gram-positive microorganisms (MICs = 0.015– 0.06 g/mL) including E. faecalis [66]. O

O F O

N

N

F

COOH N

O

N

N

COOH

N

N

N

N H

N H

73

72

O

O F O

N

N

F

COOH N

HN

N

O

N H

e

COOH

N

N

N 75

74

O

O F HN O

N

F

COOH N

N

COOH

N

N

N OMe

S

N 76

77

O O F

F N

N

NH2 N

N

N

O

H 2N 78

N

NH2 O

H 2N 79

3.9. Oxazolidinone Antibiotic The oxazolidinones were discovered at E.I. du Pont Nemours & Company in the 1980s, and later developed at Pharmacia and Upjohn (now part of Pfizer), ultimately leading to linezolid (80), and an analogue, eperezolid (81). Linezolid (80) is the only FDA-approved oxazolidinone antibacterial agent marketed for over 35 years. It is highly-effective for the treatment of serious Gram-positive infections, including those caused by S. pneumoniae, and the highly challenging MRSA and VRE [67]. Linezolid`s mechanism of action is unique [68]. Previous studies have suggested that oxazolidinones inhibit the formation of the initiation complex in bacterial translation systems by preventing the formation of the N-formylmethionyl- tRNA-ribosome- mRNA ternary complex. Recent studies revealed that oxazolidinones interact with the 50S A-site pocket at the peptidyltransferase centre (PTC) of the bacterial ribosome, which overlaps the aminoacyl moiety of an A-site bound tRNA, and therefore inhibits the overall protein synthesis process [69]. The commercial success of linezolid, the only FDAapproved oxazolidinone, has prompted many pharmaceutical companies to devote resources to this area. Until now, four types of chemically modified linezolid and oxazolidinonetype antibacterial agents, including modification on each of the A-(oxazolidinone), B-(phenyl), and C-(morpholine) rings as well as the C-5 side chain of the A-ring substructure, have been described. Four oxazolidinones tedizolid (82), radezolid (83) [68], sutezolid (84) and AZD5847 (85)) are currently undergoing clinical development [70].

33

The SAR studies from literature indicate an important role of stereochemical configuration (S) for the binding group at the C-5 position of the oxazolidinone ring [71]. Additionally, the early SAR studies determined at DuPont and at Pharmacia indicated that the C-5 acetamide arm was required for optimal antibacterial activity of the oxazolidinones, because of an interaction with the ribosome binding site. This highlights the fact that N-H participates as a hydrogen bond donor, while the ester type oxygen in the oxazolidinone ring acts as a hydrogen bond acceptor [71]. The continued exploration of the SAR of the C-5 side chain of the A-ring substructure has led to the discovery that sulphur isosteres (86-92) of the acetamidomethyl side chain and Five-membered ring heterocycles (85, 93-95) could also give highly potent analogues of oxazolidinones[72]. They exhibit more potent activity against VRE than Linezolid (80). Due to the significance of the oxazolidinone A-ring, relatively few modifications have been observed. The crystal structure of linezolid bound to the 50S ribosomal subunit has revealed that the fluorophenyl moiety sits ideally in a heteroaromatic crevice formed by the PTC site. This moiety is engaged in a typical aromatic stacking interaction with C2487 and a T-shaped interaction with the base of A2486 of 50S ribosomal subunit of Haloarcula marismortui [69]. This observation suggests that modification of the B-ring may alter the interaction with the binding site, and thus cause the loss of activity. Consequently, there have been no recent studies of B-ring modification. The morpholine ring does not appear to make significant interactions with the ribosome, suggesting that many different functional groups can be substituted for the morpholine without a significant loss of activity [71]. Accordingly, the piperazinyl phenyl oxazolidinone SAR optimization program showed that a wide range of alkyl, carbonyl, and sulphonyl substituents were tolerable on the distal piperazine nitrogen atom, indicating that the 4`-position on the C-ring is undoubtedly the most tolerant to variation [73]. Besides the substitution derivatives on the C-ring, 82-96, a benzenoheptanone derivative (97), showed the best antibacterial activities against Gram-positive pathogens including E. faecalis with MICs from 2- to 4-fold higher than linezolid[74]. Another compound, 98 (PF-708093), entered Phase I clinical trials, however the development was discontinued after one year [68]. The studies reveal that an appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone analogues (gram-positive MIC’s105 selectivity versus the human TMK homologue was achieved [79]. Pyrrolamide Antibiotics: Pyrrolamides are a novel class of antibacterial agents that target DNA gyrase, resulting in

Enterococcus and Campylobacter Infection

Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

resistant E. faecalis (VREF) with a MICs of 0.06 - 2g/ml. Dehydrohomoplatencin (109) is similar to platensimycin (108) achieved by total synthesis, which displays potent antibacterial activity with MICs of 0.12g/ml [86].

inhibition of DNA synthesis and bacterial cell death. The pyrrolamide series inhibits the enzyme by binding to the ATP pocket of GyrB, as demonstrated by an initial lead compound 102 with sub-micromolar enzyme potency but weak antibacterial activity [80]. The optimization of chemical structure through substitutions to the pyrrole, piperidine, and heterocycle portions resulted in pyrrolamides (103,104) with improved cellular activity and in vivo efficacy [81].

Uncialamycin Antibiotic: Uncialamycin (110) is a newly discovered enediyne isolated from an unspecified streptomycete strain of related to Streptomyces cyanogenus [87]. 110 and 26-epiuncialamycin (111) promote single- and doublestrand cuts in plasmid DNA and exhibit powerful antibacterial properties against several strains, including methicillinresistant S. aureus (MRSA; MIC = 0.0002 g/mL) and E. faecalis (VRE; MIC = 0.002 g/mL). In addition, they also show potent activities against a broad panel of cancer cells, including taxol-resistant ovarian cells and epothilone B resistant cells. They are potent antitumor antibiotics [88].

These compounds have potent in vitro activities against selected Gram-positive and Gram-negative pathogens, including MRSA, MRQRSA, VRE, PRSP. Representatives of the class were shown to be bactericidal and demonstrated similar frequencies of resistance to those of antibiotics clinically used. Bisanthraquione Antibiotic: The bisanthraquinone antibiotic BE-43472B [(+)-105] was isolated by Rowley and coworkers from a streptomycete strain found in a blue-green algae associated with Ecteinascidia turbinata. It has shown promising antibacterial activity against clinically derived isolates of methicillin-susceptible, methicillin-resistant, and tetracyclin-resistant Staphylococcus aureus (MSSA, MRSA, and TRSA, respectively) and VRE[82]. Its unnatural enantiomer [(-)-105] of antibiotic BE-43472B exhibited antibacterial properties comparable to those of the natural enantiomer [(+)-105] [83]. Semi-synthetic derivatives of BE-43472B [(+)-105] have also potent activities against clinical S. aureus and E. faecium isolates. The most potent antibiotic 106 displayed MIC50 values of 0.11, 0.23, and 0.90 M against a panel (n = 25 each) of clinical MSSA, MRSA, and VRE, respectively, and was determined to be bactericidal by time-kill analysis [82b].

Cyclothialidine: The DNA gyrase inhibitor cyclothialidine 112 had been shown to be a valuable lead structure for the discovery of new antibacterial classes able to overcome bacterial resistance. Dilactam analogues of 112 were also found to be potent DNA gyrase inhibitors. The dilactam inhibitors cover the same antibacterial spectrum than the monolactams and were found to be particularly active against multi-drug resistant strains of E. faecalis, E. faecium, and S. pneumonia. By optimizing bicyclic lactones derived from the natural product cyclothialidine, the 4bromodilactam 113 displayed a significantly improved pharmacokinetic behavior, which resulted in a substantial in vivo efficacy with an ED50 of 3 mg/kg in a mouse septicaemia model [89]. 4. NEW ANTIBACTERIAL AGENT AGAINST CAMPYLOBACTER

Platensimycin Antibiotic: Platensimycin (107) [84] and platencin (108) [85], represented a potential breakthrough in antibiotic research. Both compounds are potent inhibitors of the fatty acid synthesis in Gram-positive bacteria and even eradicate notoriously resistant bacteria such as methicillinresistant Staphylococcus aureus (MRSA) and vancomycin-

Through the retrieval of relevant literature, although the observed fact of an increase in the proportion of FQs and macrolides resistant Campylobacter strains worldwide potentially compromises the efficacy of antimicrobial treatment of human infection. Surprisingly, new antibacterial agents

O NH2

Cl

Cl

H N N H

H N

N N H

N

O

Cl

Cl

Cl

O

Cl

Cl

N

H N

OH

N

N H

S

O

O

O O O

104

OH

OH OH CH3 O

O

OH

H OH CH3

O H3C 106

(+) 105

OH O

O HO2C

N H

OH

HO

H 3C

HO2C

O

O O

H CH3

HO

OH O

OH

N H

O

OH O HO2C OH

N H

O 107

OH

S

O

103 OH

N N O

102

35

108

109

O

36 Current Topics in Medicinal Chemistry, 2014, Vol. 14, No. 1

Xu et al.

against Campylobacter have never been intensively explored by medicinal chemists [90]. There are very few reports on new antibacterial agent against Campylobacter [91], which may be related to the relative low resistance rate of Campylobacter. Because the compounds reported show low bioactivity, the detailed content is no longer tautology here.

[3] [4] [5]

26(R)

O

HN

O

26(S)

OH O

O

OH

OH

O

HN S

O

HO

O

OH

[7]

OH

O N OH

NH2

O

N

S HN

OH N

N H

O

O

COOH O O

HN

[6]

OH

111

110

OH

HN

O HN

MeO Br

O

HO 112

O

O

[8]

113

SUMMARY Bacterial infections increasingly evade standard treatment as resistance to multiple antibiotics is spreading throughout the world. Resistance is inevitably the result of antibiotic use and therefore limits the efficacy and life span of every antibiotic. There is an urgent medical need for a sustainable supply of new, effective, and safe antibacterial drugs without cross-resistance to currently used antibiotics. However, the commercial success of drugs against chronic diseases has tempted many companies to preferentially invest into “chronic drugs” rather than into “short-term antibacterial agents”. On the other hand, attempts to exploit novel antibacterial targets have been disappointing and the “one-target-one-disease” approach has been unsuccessful for this area. The investment in antibacterial discovery and development is flagging and many big pharmaceutical companies have exited the field. Only the persistent discovery and development of novel resistance-breaking antibacterial lead structures will guarantee future therapy. New ideas and solutions are needed that facilitate and support this endeavor.

[9]

[10] [11]

[12] [13] [14]

CONFLICT OF INTEREST The author(s) confirm that this article content has no conflicts of interest.

[15]

ACKNOWLEDGEMENTS [16]

The authors would like to thank the National Nature Science Foundation of China, No. 20902086, for financial support. REFERENCES [1] [2]

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