Antistaphylococcal Activity of WCK 771, a Tricyclic Fluoroquinolone, in Animal Infection Models

Patel, Mahesh; Souza, N. J. De; Gupte, Shrikant V.; Jafri, Mohammad Alam; Bhagwat, Sachin; Chugh, Yati; Khorakiwala, Habil F.; Jacobs, Michael; Appelbaum, Peter C.

doi:10.1128/aac.48.12.4754-4761.2004

Cited by 44 publications

(36 citation statements)

References 33 publications

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“…Specifically, tigecycline circumvents a series of major facilitator superfamily-class tetracycline-specific efflux proteins of both gram-negative and gram-positive pathogens (17,50,61), while telithromycin has significantly improved activity versus clinical isolates with elevated macrolide efflux via the MefA/E (23) and AcrAB systems (9). In the case of the fluoroquinolones, the overall hydrophilicity (3,63) and bulk (26,33,34) of these compounds affect their sensitivity to specific efflux pumps, and the apparent structure-activity relationships delineated have contributed in the identification of novel development candidates that are less prone to efflux (49). Finally, studies of the effects of overexpression of the MexAB-OprM, MexCD-OprJ, and MexXYOprM systems on the efflux of a series of closely related carbapenem-class antibiotics has revealed intricate substrate specificities that could be further exploited in directed chemistry efforts (48).…”

Section: Discussionmentioning

confidence: 99%

A Novel Indole Compound That Inhibits Pseudomonas aeruginosa Growth by Targeting MreB Is a Substrate for MexAB-OprM

Robertson¹,

Doyle²,

Du³

et al. 2007

J Bacteriol

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Drug efflux systems contribute to the intrinsic resistance of Pseudomonas aeruginosa to many antibiotics and biocides and hamper research focused on the discovery and development of new antimicrobial agents targeted against this important opportunistic pathogen. Using a P. aeruginosa PAO1 derivative bearing deletions of opmH, encoding an outer membrane channel for efflux substrates, and four efflux pumps belonging to the resistance nodulation/cell division class including mexAB-oprM, we identified a small-molecule indole-class compound (CBR-4830) that is inhibitory to growth of this efflux-compromised strain. Genetic studies established MexAB-OprM as the principal pump for CBR-4830 and revealed MreB, a prokaryotic actin homolog, as the proximal cellular target of CBR-4830. Additional studies establish MreB as an essential protein in P. aeruginosa, and efflux-compromised strains treated with CBR-4830 transition to coccoid shape, consistent with MreB inhibition or depletion. Resistance genetics further suggest that CBR-4830 interacts with the putative ATP-binding pocket in MreB and demonstrate significant cross-resistance with A22, a structurally unrelated compound that has been shown to promote rapid dispersion of MreB filaments in vivo. Interestingly, however, ATP-dependent polymerization of purified recombinant P. aeruginosa MreB is blocked in vitro in a dosedependent manner by CBR-4830 but not by A22. Neither compound exhibits significant inhibitory activity against mutant forms of MreB protein that bear mutations identified in CBR-4830-resistant strains. Finally, employing the strains and reagents prepared and characterized during the course of these studies, we have begun to investigate the ability of analogues of CBR-4830 to inhibit the growth of both efflux-proficient and efflux-compromised P. aeruginosa through specific inhibition of MreB function.The activity of efflux-based drug extrusion mechanisms impact the overall effectiveness of current antimicrobial therapies and impair efforts to discover new chemotherapeutic treatments for many serious bacterial diseases (4,42,43,65). Few bacterial pathogens exemplify the importance of the interplay between xenobiotic efflux extrusion systems and the exclusion of antimicrobial agents at the level of the poorly permeable gram-negative outer membrane quite like Pseudomonas aeruginosa (46, 58). Indeed, this organism has the capacity to encode more than 50 potential multidrug transporters including 12 resistance nodulation/cell division (RND)-class transporters, which to date, represent the only clinically significant drug transporters that have been experimentally validated for P. aeruginosa (20,58).The MexAB-OprM tripartite pump confers basal resistance to P. aeruginosa to a number of chemically distinct antibiotics (58) and through gain-of-function mutations, including those in regulatory proteins (e.g., mexR or mexZ), may overproduce MexAB-OprM or other RND-class pumps which are significant contributors to multidrug resistance in clinical P. areuginosa isolates...

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Section: Discussionmentioning

confidence: 99%

A Novel Indole Compound That Inhibits Pseudomonas aeruginosa Growth by Targeting MreB Is a Substrate for MexAB-OprM

Robertson¹,

Doyle²,

Du³

et al. 2007

J Bacteriol

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“…JNJ-Q2 was 65% orally bioavailable in dogs, monkeys (G. Eichenbaum and S. Stellar, unpublished data), and humans (J. M. Davenport, P. Covington, L. Liverman, G. McIntyre, and J. Almenoff, presented at the Annual Meeting of the American College of Clinical Pharmacology, Chicago, IL, 2011). In the mouse, an oral dose of JNJ-Q2 administered at 10 mg/kg yielded an area under the curve (AUC) of 0.13 g ⅐ h/ml (S. Steller and A. Streeter, unpublished data), a value that is 11-fold and 6-fold lower than the values seen with oral ciprofloxacin and moxifloxacin mouse exposures, respectively (23,27). In the established skin infection model, studies with ciprofloxacin and moxifloxacin included doses of 150 and 200 mg/kg, respectively, achieving exposures in the mouse comparable to human doses of 750 and 400 mg, respectively (23,26,27).…”

Section: Discussionmentioning

confidence: 96%

“…In the mouse, an oral dose of JNJ-Q2 administered at 10 mg/kg yielded an area under the curve (AUC) of 0.13 g ⅐ h/ml (S. Steller and A. Streeter, unpublished data), a value that is 11-fold and 6-fold lower than the values seen with oral ciprofloxacin and moxifloxacin mouse exposures, respectively (23,27). In the established skin infection model, studies with ciprofloxacin and moxifloxacin included doses of 150 and 200 mg/kg, respectively, achieving exposures in the mouse comparable to human doses of 750 and 400 mg, respectively (23,26,27). In the septicemia model, the lower ED 50 value for the subcutaneous administration of JNJ-Q2 in comparison to that for moxifloxacin reflects the lower MIC values for JNJ-Q2, but the lower ED 50 values for moxifloxacin following peroral administration likely resulted from its greater oral bioavailability in the mouse.…”

Section: Discussionmentioning

confidence: 96%

“…In vitro, moxifloxacin displays activity against S. pneumoniae, including some ciprofloxacin-resistant isolates carrying quinolone resistance-determining region (QRDR) mutations; however, the MICs of JNJ-Q2 were 32-fold lower than those of moxifloxacin for these S. pneumoniae isolates (24). The greater in vitro potency of JNJ-Q2 was reflected in the relative activities of these agents in the murine lower respiratory tract infection model, in which JNJ-Q2 displayed lower ED 50 (27). In the septicemia model with MRSA, JNJ-Q2 was more active than either of the anti-MRSA agents linezolid or vancomycin.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of a New Fluoroquinolone, JNJ-Q2, in Murine Models of Staphylococcus aureus and Streptococcus pneumoniae Skin, Respiratory, and Systemic Infections

Fernandez¹,

Hilliard²,

Morrow³

et al. 2011

Antimicrob Agents Chemother

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The in vivo efficacy of JNJ-Q2, a new broad-spectrum fluoroquinolone (FQ), was evaluated in a murine septicemia model with methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) and in a Streptococcus pneumoniae lower respiratory tract infection model. JNJ-Q2 and comparators were also evaluated in an acute murine skin infection model using a community-acquired MRSA strain and in an established skin infection (ESI) model using a hospital-acquired strain, for which the selection of resistant mutants was also determined. JNJ-Q2 demonstrated activity in the MSSA septicemia model that was comparable to that moxifloxacin (JNJ-Q2 50% effective dose [ED 50 Successive improvements in the spectrum and antimicrobial potency of agents in the fluoroquinolone class have resulted in widespread clinical utility of these agents, and the activities of levofloxacin and moxifloxacin against Gram-positive pathogens, particularly Streptococcus pneumoniae, have contributed to the adoption of these agents for the empirical treatment of respiratory tract infections in the community setting. Although fluoroquinolone resistance in S. pneumoniae remains low, with the rate of levofloxacin resistance in U.S. isolates typically reported at less than 1% (12), the rate of fluoroquinolone resistance has, in selected populations or geographic regions, been reported to be greater than 10% (1). In association with the introduction of the seven-valent pneumococcal vaccine (PCV7), an increased prevalence in non-PCV7 serotypes has been observed (11, 12), including several predominant fluoroquinolone-resistant and multidrug-resistant clones (4, 10). Several of the marketed fluoroquinolone agents also display in vitro activity against Staphylococcus aureus isolates and have been used successfully to treat staphylococcal infections (31), although none of these marketed agents are approved for the treatment of methicillin-resistant S. aureus (MRSA) infections. MRSA has become an increasingly important pathogen in community infections (19), and the increased incidence of infection is associated with elevated resistance, with levofloxacin resistance observed in 70% of recent U.S. clinical MRSA isolates (18). Community staphylococcal isolates typically express elevated levels of several virulence determinants, which are associated with increased virulence in murine models of bacteremia and skin abscess infection (20). Efficacy in murine models of MRSA infection is a key attribute for new antibacterial agents targeted for the treatment of staphylococcal infections, including MRSA infections in the community setting. Several investigational fluoroquinolones active against MRSA (2,5,15,17,32) are reported to be the subject of ongoing clinical studies that are investigating their efficacy in the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by MRSA. The development of new fluoroquinolone agents retaining activity against multidrug-resistant S. pneumoniae isolates and displaying potent a...

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“…S1 in the supplementary material). For WCK 771, the cidal concentrations fall in the clinically relevant range since it achieves an unbound maximum concentration of 4 g/ml with a half-life of 6 h when it is used at the therapeutic dose in humans and has been proposed to have a PK-PD breakpoint of 2 g/ml, on the basis of the findings of in vivo studies (2,26) (Table S4 in the supplemental material). We have also established that WCK 771 effected the killing of a variety of double mutants at a CLSI-recommended starting inoculum over a concentration range of 1 to 2 g/ml (data not shown).…”

Section: Discussionmentioning

confidence: 99%

The Anti-Methicillin-Resistant Staphylococcus aureus Quinolone WCK 771 Has Potent Activity against Sequentially Selected Mutants, Has a Narrow Mutant Selection Window against Quinolone-Resistant Staphylococcus aureus , and Preferentially Targets DNA Gyrase

Bhagwat

Mundkur

Gupte

et al. 2006

Antimicrob Agents Chemother

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WCK 771 is a broad-spectrum fluoroquinolone with enhanced activity against quinolone-resistant staphylococci. To understand the impact of the target-level interactions of WCK 771 on its antistaphylococcal pharmacodynamic properties, we determined the MICs for genetically defined mutants and studied the mutant prevention concentrations (MPCs), the frequency of mutation, and the cidality against the wild type and double mutants. There was a twofold increase in the MICs of WCK 771 for single gyrA mutants, indicating that DNA gyrase is its primary target. All first-and second-step mutants selected by WCK 771 revealed gyrA and grlA mutations, respectively. The MICs of WCK 771 and clinafloxacin were found to be superior to those of other quinolones against strains with double and triple mutations. WCK 771 was also cidal for high-density double mutants at low concentrations. WCK 771 and clinafloxacin showed narrow mutant selection windows compared to those of the other quinolones. Against a panel of 50 high-level quinolone-resistant clinical isolates of staphylococci (ciprofloxacin MIC > 16 g/ml), the WCK 771 MPCs were <2 g/ml for 68% of the strains and <4 g/ml for 28% of the strains. Our results demonstrate that gyrA is the primary target of WCK 771 and that it has pharmacodynamic properties remarkably different from those of quinolones with dual targets (garenoxacin and moxifloxacin) and topoisomerase IV-specific quinolones (trovafloxacin). WCK 771 displayed an activity profile comparable to that of clinafloxacin, a dual-acting quinolone with a high affinity to DNA gyrase. Overall, the findings signify the key role of DNA gyrase in determining the optimal antistaphylococcal features of quinolones.Multidrug-resistant gram-positive bacteria are a growing problem in both hospitals and the community. Methicillinresistant Staphylococcus aureus (MRSA) was first reported sporadically in Europe beginning in 1961 and over the span of the last 15 years has emerged as a major multidrug-resistant pathogen worldwide (17).Quinolones interact with type II topoisomerases, DNA gyrase, and topoisomerase IV (topo IV) to execute their bactericidal activity. In S. aureus, quinolone resistance occurs stepwise by mutations in the two target topoisomerase enzymes, with the first mutation usually occurring in topo IV, followed by a mutation in DNA gyrase, due to the preferential affinities of the currently used quinolones to topo IV (31). With the increasing use of older quinolones, resistance in staphylococci has emerged rather quickly, and therefore, it is desirable that new quinolones be optimized against staphylococci carrying multiple resistance mechanisms, particularly the ones manifested through mutations in both the target genes. A higher affinity toward mutated targets results in higher potency and a lower frequency of mutation (FM). From a pharmacodynamic (PD) angle, one of the parameters of quinolone optimization would be lower, therapeutically attainable mutant prevention concentrations (MPCs) for quinolone-resistant strains that...

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Antistaphylococcal Activity of WCK 771, a Tricyclic Fluoroquinolone, in Animal Infection Models

Cited by 44 publications

References 33 publications

A Novel Indole Compound That Inhibits Pseudomonas aeruginosa Growth by Targeting MreB Is a Substrate for MexAB-OprM

A Novel Indole Compound That Inhibits Pseudomonas aeruginosa Growth by Targeting MreB Is a Substrate for MexAB-OprM

Efficacy of a New Fluoroquinolone, JNJ-Q2, in Murine Models of Staphylococcus aureus and Streptococcus pneumoniae Skin, Respiratory, and Systemic Infections

The Anti-Methicillin-Resistant Staphylococcus aureus Quinolone WCK 771 Has Potent Activity against Sequentially Selected Mutants, Has a Narrow Mutant Selection Window against Quinolone-Resistant Staphylococcus aureus , and Preferentially Targets DNA Gyrase

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