Phenylhydrazones are active against non-replicatingMycobacterium tuberculosis

Abstract

There is an urgent need for the development of shorter, simpler and more tolerable drugs to treat antibiotic tolerant populations of Mycobacterium tuberculosis. We previously identified a series of phenylhydrazones (PHY) active against M. tuberculosis. We selected six representative compounds for further analysis. All compounds were active against non-replicating M. tuberculosis, with two compounds demonstrating greater activity under hypoxic conditions than aerobic culture. Compounds had bactericidal activity with MBC/MIC of <4 and demonstrated an inoculum-dependent effect against aerobically replicating bacteria. Bacterial kill kinetics demonstrated a faster rate of kill against nonreplicating bacilli generated by nutrient starvation. Compounds had limited activity against other bacterial species. In conclusion, we have demonstrated that the PHY compounds have some attractive properties in terms of their anti-tubercular activity. KeywordsMycobacterium tuberculosis, antibiotic tolerance, bactericidal, non-replicating bacteria enters a non-replicating state that is tolerant to isoniazid, but sensitive to metronidazole [8][9][10][11][12][13].The prevalence of latent TB has complicated our ability to eradicate the disease. There is an urgent need for the development of shorter, simpler and more tolerable drug regimens to treat various subpopulations of M. tuberculosis. In order to attain a shorter therapy period, new drugs should be bactericidal and be efficacious against nonreplicating and antibiotic tolerant forms of M. tuberculosis. The hydrazone linker (-NH-N=CH-) is a useful synthetic tool enabling the generation of hydrazide-hydrazone derivatives, many of which are pharmacologically-active. Such molecules target wide range of diseases and have anti-microbial, anti-cancer, antimalarial and anti-inflammatory activities [15-29]. While the mode of action of hydrazones varies depending upon the structural characteristics, several are involved in covalent modification of proteins and/or sequestering of metal ions. Isoniazid (INH), a first line TB drug is a hydrazine, which is a tight-binding inhibitor of enoyl reductase (InhA) in M. tuberculosis; INH is a prodrug which requires activation by the KatG catalase-peroxidase [30-32]. Another anti-tubercular hydrazine, thiacetazone (TAC) covalently modifies hydroxyl-acyl-dehydratases (HadAB and HadBC) following activation by the mono-oxygenase EthA and hydroxymycolate synthase (MmaA4) [33-35]. More recently, 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone, was identified as a selective inhibitor of M. tuberculosis methionine aminopeptidase (MetAPs) with activity against replicating and non-replicating bacteria [36]. In addition, quinolone hydrazone derivatives are currently being explored as potential anti-cancer and antitubercular drugs [37]. Interestingly, copper (II) and zinc (II) complexes of quinolone hydrazone derivatives have higher anti-tubercular activity than the free hydrazone [37].We previously identified a series of phenylhydrazones (PHY) in a target-base...