About this Research Topic
The emergence and spread of drug-resistance in Mycobacterium tuberculosis (Mtb) threatens global efforts to control tuberculosis (TB), an airborne disease which remains among the biggest infectious killers globally. Treatment of drug-susceptible TB with the four-drug combination of isoniazid (INH), pyrazinamide, rifampicin (RIF), and ethambutol for two months, followed by a combination of INH and RIF for four months, limits the emergence of resistance and disease relapse. Despite the efficacy of this frontline regimen, the WHO estimates that in 2019 over 450,000 of the 10 million new TB cases were RIF monoresistant or multidrug-resistant (MDR) TB. Treatment of patients infected with MDR Mtb strains requires extended regimens comprising second- and/ or third-line drugs associated with toxic side effects and poor cure rates (57% for MDR Mtb). Encouragingly, the FDA recently approved a combination therapy of bedaquiline, pretomanid, and linezolid for the treatment of extensively drug-resistant (XDR) TB - defined as MDR TB plus resistance to a fluoroquinolone and any of the second-line injectable aminoglycosides - which reduced average treatment times from 24 to 6 months, a milestone that highlights the importance of pursuing drug discovery and identifying novel drug targets.
As an obligate human pathogen, Mtb poses a number of unique challenges, and recent work on clinical TB drugs or compounds in preclinical hit-to-lead development has highlighted how much is still to be learnt about the biology of Mtb and the mechanisms of resistance against the drugs that target Mtb. Canonical mechanisms of drug resistance (such as drug efflux, drug metabolism, target modification, and inhibition of drug uptake) are only part of the problem: Mtb’s biology and drug resistance are profoundly influenced by microenvironments encountered in the host and the chemistries of host immunity. During infection, Mtb may be exposed to conditions that impact its susceptibility to antibiotics, including metal starvation or intoxication, acidic conditions, carbon sources such as cholesterol and other lipids, hypoxia, and reactive oxygen and/or nitrogen species. How host immunity impacts both genetic and non-genetic drug resistance remains very poorly understood. The unmasking of viable Mtb that are differentially detectable/culturable - that is, bacilli that fail to grow on bacteriologic solid media, yet can be enumerated by limiting dilution and most probable number calculations - highlights an urgent need to develop new approaches to characterize the impact of antibiotics and host immunity on Mtb and re-evaluate how we design experiments and clinical trials.
This research collection aims to provide a state-of-the-art update of the key research avenues under exploration in attempting to address the problem of Mtb drug-resistance. We welcome reviews and primary articles about resistance of genetic origin (intrinsic and acquired), and resistance of non-genetic origin (phenotypic drug resistance). Owing to the intimacy and complexity of the host-pathogen interaction, we seek submissions that consider the problem from different perspectives (host and pathogen) and disciplines (microbiology, immunology, clinical infectious disease, chemistry, etc.). Reviews and articles should identify and address critical gaps in knowledge of Mtb biology and drug discovery that relate to drug resistance and provide roadmaps to translate this knowledge to the clinic.
● Drug resistance
● Phenotypic drug resistance
● Differentially detectable/culturable Mtb
● Genetic determinants of drug susceptibility
● The contribution of in vivo drug distribution to drug resistance
● Characterizing the biology of drug-resistant Mtb (genetic and non-genetic), ranging from systems biology to single-cell analyses
● Mtb drug discovery to address resistance
● Evolution and spread of drug-resistant Mtb
● Role of host immunology in Mtb drug resistance
● Host-directed therapy in treating drug-resistant Mtb
● Alternative therapeutic regimens and approaches (e.g., drug holidays) for treatment of drug-resistant Mtb
Keywords: Mycobacterium tuberculosis, tuberculosis, drug resistance, antimicrobial resistance, genetic drug resistance, immunity, phenotypic drug resistance
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