A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Locher, Christopher P.; Jones, Steven M.; Hanzelka, Brian L.; Perola, Emanuele; Shoen, Carolyn; Cynamon, Michael H.; Ngwane, Andile H.; Wiid, Ian; Helden, Paul D. van; Betoudji, Fabrice; Nuermberger, Eric L.; Thomson, John A.

doi:10.1128/aac.04347-14

Cited by 71 publications

(107 citation statements)

References 33 publications

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“…The relationship between acquired moxifloxacin resistance and the moxifloxacin AUC/MIC was best described by a quadratic function, similar to our findings with M. tuberculosis (25). However, the underlying mechanism for moxifloxacin resistance in M. abscessus deserves further exploration; DNA gyrase is still an interesting bacterial target against which new inhibitors are being developed, with evaluation of their potential for use against M. abscessus and other nontuberculous mycobacteria (42).…”

Section: Discussionsupporting

confidence: 69%

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease

Ferro

Srivastava

Deshpande

et al. 2016

Antimicrob Agents Chemother

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f Current regimens used to treat pulmonary Mycobacterium abscessus disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which M. abscessus was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our M. abscessus strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (k el ) of 0.11 ؎ 0.05 h ؊1 (mean ؎ standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (E max ) modeling revealed that the highest E max was 3.15 ؎ 1.84 log 10 CFU/ml on day 3, and the exposure mediating 50% of E max (EC 50 ) was a 0-to 24-h area under the concentration time curve (AUC 0 -24 )-to-MIC ratio of 41.99 ؎ 31.78 (r 2 ‫؍‬ 0.99). The EC 80 was an AUC 0 -24 /MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC 0 -24 /MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400-to 800-mg/day doses would achieve or exceed the EC 80 in <12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all M. abscessus clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin's efficacy against M. abscessus was poor, formal combination therapy studies with moxifloxacin are still recommended. Mycobacterium abscessus is a rapidly growing mycobacterium that is notorious because of resistance to most antibiotics (1). Pulmonary disease due to M. abscessus infection is chronic and relentless. Current regimens used to treat M. abscessus consist of a combination of amikacin, a macrolide, and either cefoxitin or imipenem; however, the regimens fail in most patients (2). Based on static in vitro models, amikacin is considered the key antibiotic in the treatment regimens (3-6). We recently demonstrated that the efficacy of amikacin based on concentration-time profiles achievable in human lungs as recapitulated in the hollow-fibersystem model of M. abscessus (HFS-M. abscessus) was poor, with failure to kill the bacteria below stasis (7). This, as well as clinical experience of high failure rates of amikacin-based regimens, means that there is an urgent need to find new antibiotics and optimize their doses. Here, we approached this by conducting a recommended formal pharmacokinetic/pharmacodynamic (PK/ PD) evaluation of alternative antibiotics with potential bactericidal activity (8).The 8-methoxy fluoroquinolone, moxifloxacin, has been shown to have excellent efficacy against Mycobacterium tub...

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Section: Discussionsupporting

confidence: 69%

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease

Ferro

Srivastava

Deshpande

et al. 2016

Antimicrob Agents Chemother

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“…Studies using multiple animal models have shown that bedaquiline is efficacious against M. tuberculosis, Mycobacterium leprae, and to some extent M. avium (25,(35)(36)(37). Bedaquiline potently inhibits the mycobacterial enzyme complex ATP synthase, thus interfering with energy production and homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of Mycobacterium abscessus to Antimycobacterial Drugs in Preclinical Models

Obregón-Henao

Arnett

Henao-Tamayo

et al. 2015

Antimicrob Agents Chemother

106

144

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bOver the last 10 years, Mycobacterium abscessus group strains have emerged as important human pathogens, which are associated with significantly higher fatality rates than any other rapidly growing mycobacteria. These opportunistic pathogens are widespread in the environment and can cause a wide range of clinical diseases, including skin, soft tissue, central nervous system, and disseminated infections; by far, the most difficult to treat is the pulmonary form. Infections with M. abscessus are often multidrug-resistant (MDR) and require prolonged treatment with various regimens and, many times, result in high mortality despite maximal therapy. We report here the evaluation of diverse mouse infection models for their ability to produce a progressive high level of infection with M. abscessus. The nude (nu/nu), SCID (severe combined immunodeficiency), gamma interferon knockout (GKO), and granulocyte-macrophage colony-stimulating factor (GMCSF) knockout mice fulfilled the criteria for an optimal model for compound screening. Thus, we set out to assess the antimycobacterial activity of clarithromycin, clofazimine, bedaquiline, and clofazimine-bedaquiline combinations against M. abscessus-infected GKO and SCID murine infection models. Treatment of GKO and SCID mice with a combination of clofazimine and bedaquiline was the most effective in decreasing the M. abscessus organ burden.

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“…Figure 14. The two subclasses of benzimidazole ureas, with their optimal properties for reduced serum shift [78][79][80].…”

Section: Inhibitors Focused On Mycobacterium Tuberculosis Dna Gyrasementioning

confidence: 99%

Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors

2018

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New antibacterials that modulate less explored targets are needed to fight the emerging bacterial resistance. DNA gyrase and topoisomerase IV are attractive targets in this search. These are both type II topoisomerases that can cleave both DNA strands, and can thus alter DNA topology during replication or similar processes. Currently, there are no ATP-competitive inhibitors of these two enzymes on the market, as the only aminocoumarin representative, novobiocin, was withdrawn due to safety concerns. The search for novel ATP-competitive inhibitors is a focus of ongoing industrial and academical research. This review summarizes the recent efforts in the design, synthesis and evaluation of GyrB/ParE inhibitors. The various approaches to achieve improved antibacterial activities are described, with particular reference to Gram-negative bacteria.

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A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Cited by 71 publications

References 33 publications

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease

Susceptibility of Mycobacterium abscessus to Antimycobacterial Drugs in Preclinical Models

Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors

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