The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs

Abstract

Tuberculosis (TB) poses an enduring threat to global health. Consistently ranked among the top 10 causes of death worldwide since 2000, TB has now exceeded HIV-AIDS in terms of deaths inflicted by a single infectious agent. In spite of recently declining TB incident rates, these decreases have been incremental and fall short of threshold levels required to end the global TB epidemic. As in other infectious diseases, the emergence of resistant organisms poses a major impediment to effective TB control. Resistance in mycobacteria may evolve from genetic mutations in target genes which are transmitted during cell multiplication from mother cells to their progeny. A more insidious form of resistance involves sub-populations of non-growing (“dormant”) mycobacterial persisters. Quiescent and genetically identical to their susceptible counterparts, persisters exhibit non-inheritable drug tolerance. Their prevalence account for the protracted treatment period that is required for the treatment of TB. In order to improve the efficacy of treatment against mycobacterial persisters and drug-resistant organisms, novel antitubercular agents are urgently required. Selective targeting of bacterial membranes has been proposed as a viable therapeutic strategy against infectious diseases. The underpinning rationale is that a functionally intact cell membrane is vital for both replicating and dormant bacteria. Perturbing the membrane would thus disrupt a multitude of embedded targets with lethal pleiotropic consequences, besides limiting the emergence of resistant strains. There is growing interest in exploring small molecules as selective disruptors of the mycobacterial membrane. In this review, we examined the recent literature on different chemotypes with membrane perturbing properties, the mechanisms by which they induce membrane disruption and their potential as anti-TB agents. Cationic amphiphilicity is a signature motif that is required of membrane targeting agents but adherence to this broad physical requirement does not necessarily translate to conformity in terms of biological outcomes. Nor does it ensure selective targeting of mycobacterial membranes. These are unresolved issues that require further investigation.

Extreme Drug Tolerance of Mycobacterium abscessus “Persisters”

“…The new "persister" culture models we developed here are intended to be used as secondary whole cell assays in Mab drug discovery flowcharts to complement standard MIC and MBC 90 profiling of new anti-mycobacterial agents. The mycobacterial membrane and its associated functions recently gained interest as target space (Chen et al, 2018). For instance, several diverse chemotypes were found to show attractive potency against M. tuberculosis and Mab by inhibiting the essential mycolic Broth MIC, MIC for aerated nutrient-rich planktonic culture (see Figure 1C).…”

An in vitro ADME and in vivo Pharmacokinetic Study of Novel TB-Active Decoquinate Derivatives

“…Decoquinate (DQ) (6-decoxy-7-ethoxy-4-oxo-1 H -quinoline-3-carboxylic acid ethyl ester, DQ; Figure 1), an anticoccidial quinolone, has been used in poultry feed for over 50 years [European Food Safety Authority (EFSA), 2003; Taylor and Bartram, 2012]. Although DQ is inactive against Mtb , the lipophilic decyl side chain of the derivatives should allow permeation through the mycolic acid cell wall of Mtb , infected macrophages, and granulomatous lesions containing Mtb by passive diffusion (Hurdle et al, 2011; Chen et al, 2018). However, DQ shows poor drug-like properties, including low solubility in water (0.06 mg L -1 ) and in aqueous buffer at pH 4.9 (<0.01 mg L -1 ) [European Food Safety Authority (EFSA), 2003].…”

Evaluation of the Antimicrobial Effect of the Extracts of the Pods of Piliostigma thonningii (Schumach.) Milne-Redh. (Fabaceae)

“…Due to the development of mycobacterial persisters as well as antimycobacterial resistance, alternative treatment regimens are urgently required. The disruption of the bacterial membrane by chemical agents has emerged as an effective means to eradicate or inhibit the growth of bacteria, thereby, allowing the treatment and reduction of infectious diseases [ 53 ]. Most antifungal agents have been developed to primarily inhibit enzymes that are involved in the biosynthesis of the fungal cell membrane components such as phospholipid, sphingolipid, and ergosterol [ 54 ].…”