Clade-Specific Distribution of Antibiotic Resistance Mutations in the Population of Mycobacterium tuberculosis - Prospects for Drug Resistance Reversion

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a leading cause of death in humans worldwide. The emergence of antibiotic-resistant strains of Mtb is a threat to tuberculosis control. A general belief is that drug resistance is acquired by Mtb during antibiotic treatment by accumulation of spontaneous mutations. Also, it is known that the drug resistance mutations (DRM) have an associated fitness cost, reducing the transmissibility and virulence of resistant strains. In this work we show that many canonical DRM are clade specific; i.e. they occur only in specific genetic lineages of Mtb and depend on a specific genetic context necessary for the reduction of the fitness cost and sustainability of the drug resistance phenotype. Dependence of the drug resistance on occurrence of genetic variants of multiple genes and specific activities of the encoded proteins allows combating the drug resistance by impairing the global genetic context. A new drug, FS-1, reverses antibiotic resistance by compromising this genetic context and aggravating the fitness cost of DRM.

The Effect of Iodine-Containing Nano-Micelles, FS-1, on Antibiotic Resistance, Gene Expression and Epigenetic Modifications in the Genome of Multidrug Resistant MRSA Strain Staphylococcus aureus ATCC BAA-39

“…The latter approach was discussed and modeled in the review by Baym et al (2016); however, these authors did not gain deep insight into possible molecular mechanisms of counter-selecting against drug resistance in bacterial populations because of absence of workable models. The introduction of FS-1 into clinical practice (Ilin and Kulmanov, 2014;Ilin et al, 2017;Korotetskiy et al, 2017;Islamov et al, 2018;van Niekerk et al, 2018) allowed detail investigation of this phenomenon. A series of experiments on selected multidrug resistant model microorganisms was performed, first on E. coli ATCC BAA-196 (Korotetskiy et al, 2020b) and currently on S. aureus ATCC BAA-39.…”

“…Drug combinations are also currently being used in most treatments of infectious diseases (Poulikakos et al, 2014). Drug-induced reversion of antibiotic-resistant pathogens into sensitive phenotypes is a prospective approach to target the mechanisms and evolution of bacterial resistance (Baym et al, 2016;Ilin et al, 2017;van Niekerk et al, 2018).…”

“…As epigenetic modifications are so important for the virulence and antibiotic resistance of pathogenic bacteria, the possibility of using the phase variation processes and epigenetic modifications to induce and direct antibiotic resistance reversion in populations of multidrug resistant pathogens may be assumed; however, it has never been explored. Recently, a new medicine, FS-1, was introduced into clinical practice as a supplement to antibiotic therapy for drug-resistant tuberculosis (Ilin and Kulmanov, 2014;Ilin et al, 2017;Korotetskiy et al, 2017;Islamov et al, 2018;van Niekerk et al, 2018). FS-1 is an iodine-containing nanomicelle, which reverses the susceptibility of resistant pathogens to conventional antibiotics.…”

The Epistatic Landscape of Antibiotic Resistance of Different Clades of Mycobacterium tuberculosis

“…According to a report by the World Health Organization (WHO) in 2017, approximately 4.1% of new TB cases and 19% of previously treated cases were classified as multidrug-resistant TB (MDR-TB). MDR-TB can be classified as resistance to first-line drugs isoniazid and rifampicin, and ultimately, extensive drug resistance (XDR) is resistance to first-line drugs and at least one second-line drug, i.e., amikacin, kanamycin, capreomycin or one of the fluoroquinolones [3,4]. Treatment for patients with MDR and XDR is often accompanied by prolonged and costly antibiotic courses and poor outcomes that result in high rates of mortality and treatment failure [5,6].…”

“…Focusing exclusively on DR-associated mutations uncovers the whole complexity of the antibiotic resistance evolution in TB. Patterns of distribution of DR mutations in TB genomes appeared to be lineage specific due to epistasis limitations [3,17,18]. When a DR mutation is acquired, it is expected that this would impose a fitness cost.…”