Central carbon metabolism remodeling as a mechanism to develop drug tolerance and drug resistance in Mycobacterium tuberculosis

Abstract

Suboptimal efficacy of the current antibiotic regimens and frequent emergence of antibiotic-resistant Mycobacterium tuberculosis (Mtb), an etiological agent of tuberculosis (TB), render TB the world’s deadliest infectious disease before the COVID-19 outbreak. Our outdated TB treatment method is designed to eradicate actively replicating populations of Mtb. Unfortunately, accumulating evidence suggests that a small population of Mtb can survive antimycobacterial pressure of antibiotics by entering a “persister” state (slowly replicating or non-replicating and lacking a stably heritable antibiotic resistance, termed drug tolerance). The formation of drug-tolerant Mtb persisters is associated with TB treatment failure and is thought to be an adaptive strategy for eventual development of permanent genetic mutation-mediated drug resistance. Thus, the molecular mechanisms behind persister formation and drug tolerance acquisition are a source of new antibiotic targets to eradicate both Mtb persisters and drug-resistant Mtb. As Mtb persisters are genetically identical to antibiotic susceptible populations, metabolomics has emerged as a vital biochemical tool to differentiate these populations by determining phenotypic shifts and metabolic reprogramming. Metabolomics, which provides detailed insights into the molecular basis of drug tolerance and resistance in Mtb, has unique advantages over other techniques by its ability to identify specific metabolic differences between the two genetically identical populations. This review summarizes the recent advances in our understanding of the metabolic adaptations used by Mtb persisters to achieve intrinsic drug tolerance and facilitate the emergence of drug resistance. These findings present metabolomics as a powerful tool to identify previously unexplored antibiotic targets and improved combinations of drug regimens against drug-resistant TB infection.

Is aromatic plants environmental health engineering (APEHE) a leverage point of the earth system?

“…Defective PEPCK activity has been demonstrated to cause drug resistance through PEP depletion. However, PEP supplementation considerably reduces both antibiotic-induced persister formation and drug resistance mutations [ 165 ]. Our experiment's outcomes are corroborated by these findings.…”

Mycobacteriumdormancy and antibiotic tolerance within the retinal pigment epithelium of ocular tuberculosis

“…The World Health Organization (WHO) recommends a 6-month 2RHZE-4RH regimen comprising rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E) for the initial 2 months, followed by RH for subsequent 4 months. 7,8 The necessity for such an extended treatment course is primarily attributed to the well-documented mycobacterial dormancy and the high antibiotic tolerance associated with latent TB infection. Conventional TB chemotherapy struggles to eradicate the bacilli effectively, and thus surviving bacilli can regrow when the antibiotic effects wane or when resistant mutants emerge.…”

Metabolic Rewiring of Mycobacterium tuberculosis upon Drug Treatment and Antibiotics Resistance

“…The drug effectiveness may be affected by glpK frameshift mutations that reduce growth, alter the cellular structure, and promote the expression of stress response regulators (such as DosR and SigH) [ 125 , 126 ]. Multiple metabolic networks within Mtb , which are related to central carbon metabolism and carbon fluxes, are rewired to reduce the drug-induced stress [ 127 ]. A recently published article showed the role of cAMP signaling in intrinsic drug resistance, which unravels a whole new avenue of research in this area [ 128 ].…”