Pentacyclic Nitrofurans with In Vivo Efficacy and Activity against Nonreplicating Mycobacterium tuberculosis

Rakesh Rakesh,Bernd Meibohm,Dora B Madhura,Anne J Lenaerts,Julian G Hurdle,Michael R Mcneil,Richard E Lee,Lisa K Woolhiser,Michael S Scherman,Marcus M Maddox,Robin B Lee,Aman P Singh,David F Bruhn,Gunnar F Kaufmann

doi:10.1371/journal.pone.0087909

Abstract

The reductively activated nitroaromatic class of antimicrobials, which include nitroimidazole and the more metabolically labile nitrofuran antitubercular agents, have demonstrated some potential for development as therapeutics against dormant TB bacilli. In previous studies, the pharmacokinetic properties of nitrofuranyl isoxazolines were improved by incorporation of the outer ring elements of the antitubercular nitroimidazole OPC-67683. This successfully increased stability of the resulting pentacyclic nitrofuran lead compound Lee1106 (referred to herein as 9a). In the current study, we report the synthesis and antimicrobial properties of 9a and panel of 9a analogs, which were developed to increase oral bioavailability. These hybrid nitrofurans remained potent inhibitors of Mycobacterium tuberculosis with favorable selectivity indices (>150) and a narrow spectrum of activity. In vivo, the pentacyclic nitrofuran compounds showed long half-lives and high volumes of distribution. Based on pharmacokinetic testing and lack of toxicity in vivo, 9a remained the series lead. 9a exerted a lengthy post antibiotic effect and was highly active against nonreplicating M. tuberculosis grown under hypoxia. 9a showed a low potential for cross resistance to current antitubercular agents, and a mechanism of activation distinct from pre-clinical tuberculosis candidates PA-824 and OPC-67683. Together these studies show that 9a is a nanomolar inhibitor of actively growing as well as nonreplicating M. tuberculosis.

Highlights

Mycobacterium tuberculosis remains an important global pathogen that is believed to have infected a third of the world’s population and kills over a million persons annually [1]
Activity of nitrofurans against M. tuberculosis H37Rv mutants deficient in enzymes required for bioreductive activation of PA-824. doi:10.1371/journal.pone.0087909.t007
Given the success of nitroaromatic antibiotics in treating anaerobic bacterial infections and the current lack of suitable therapeutics to treat persistent tuberculosis infections, we report here the synthesis and antimicrobial characterization of pentacyclic nitrofuran analogs that incorporate the outer ring elements of OPC-67683

Summary

Introduction

Mycobacterium tuberculosis remains an important global pathogen that is believed to have infected a third of the world’s population and kills over a million persons annually [1]. Poor patient compliance to this lengthy drug regimen can lead to patient relapse and promotes the emergence of drug-resistant strains, which have become a major treatment challenge and global health threat. Tuberculosis strains resistant to isoniazid and rifampin, two of the most powerful antituberculosis agents, are classified as multi drug-resistant (MDR TB). It has been widely postulated that the key to decreasing treatment times and the spread of drug-resistant tuberculosis is the development of new therapeutics that target dormant bacilli, which are metabolically inactive cells that display phenotypic (non-genetic) resistance to most drugs [5]. It is imperative that novel antitubercular agents target these persisting bacterial subpopulations [6,7]

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Conclusion