The within-host evolution of antimicrobial resistance in Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) has been responsible for the greatest number of human deaths due to an infectious disease in general, and due to antimicrobial resistance (AMR) in particular. The etiological agents of human TB are a closely-related group of human-adapted bacteria that belong to the Mycobacterium tuberculosis complex (MTBC). Understanding how MTBC populations evolve within-host may allow for improved TB treatment and control strategies. In this review, we highlight recent works that have shed light on how AMR evolves in MTBC populations within individual patients. We discuss the role of heteroresistance in AMR evolution, and review the bacterial, patient and environmental factors that likely modulate the magnitude of heteroresistance within-host. We further highlight recent works on the dynamics of MTBC genetic diversity within-host, and discuss how spatial substructures in patients’ lungs, spatiotemporal heterogeneity in antimicrobial concentrations and phenotypic drug tolerance likely modulates the dynamics of MTBC genetic diversity in patients during treatment. We note the general characteristics that are shared between how the MTBC and other bacterial pathogens evolve in humans, and highlight the characteristics unique to the MTBC.

Multi-step vs. single-step resistance evolution under different drugs, pharmacokinetics, and treatment regimens

“…One aspect of resistance evolution that is especially important when considering multiple mutations is the mutational diversity that arises in the pathogen population: high genetic diversity (here meaning diversity in the resistance phenotype) increases the probability that some individuals will be able to survive a given environment – such as treatment with other drugs ( Castro et al, 2020 ) – and increases the adaptive potential overall ( Van Egeren et al, 2018 ). Using the Shannon index to determine the highest mutational diversity obtained in the population over the treatment period, we clearly observed higher diversity with single-step than multi-step resistance evolution ( Figure 2B ), even if we increased the mutation rate proportionally to the number of mutations required ( Figure 2—figure supplement 2 ).…”

“…We focus on resistance by de novo mutations as long-lasting infections such as those caused by Pseudomonas aeruginosa become hard to treat due to resistance evolving via mutations within the host during the course of the treatment 12 . Another example is Tuberculosis, arguably the infectious disease that has caused the highest number of deaths globally 13 .…”

“…We focus on resistance by de novo mutations as long-lasting infections such as those caused by Pseudomonas aeruginosa become hard to treat due to resistance evolving via mutations within the host during the course of the treatment ( Oliver et al, 2000 ). Another example is tuberculosis (TB), arguably the infectious disease that has caused the highest number of deaths globally ( Castro et al, 2020 ). During persistent TB infections, drug resistance evolves by chromosomal mutations while resistance by horizontal gene transfer (HGT) has not been observed ( Castro et al, 2020 ).…”

“…Another example is tuberculosis (TB), arguably the infectious disease that has caused the highest number of deaths globally ( Castro et al, 2020 ). During persistent TB infections, drug resistance evolves by chromosomal mutations while resistance by horizontal gene transfer (HGT) has not been observed ( Castro et al, 2020 ). HGT is a common path to resistance in hospital-acquired infections and in cases of shorter treatment durations, as exemplified by Staphylococcus epidermidis infections that became resistant by acquiring plasmids carrying genes for linezolid resistance ( Dortet et al, 2018 ).…”

Screening of Compounds for Anti-tuberculosis Activity, and in vitro and in vivo Evaluation of Potential Candidates

“…The treatment regimen for TB mainly comprises antibiotics such as rifampicin (RIF), isoniazid (INH), ethambutol, pyrazinamide, and aminoglycosides ( Fatma et al, 2020 ). Therapy with these antibiotics must be taken for 6 months to 2 years, which can result in the emergence of drug resistance and poor therapeutic outcomes ( Adams et al, 2011 ; Akos et al, 2015 ; Castro et al, 2020 ). With the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains ( Tao et al, 2017 ; Arthur et al, 2019 ), tackling the disease using currently available therapeutic regimens is a huge challenge ( Koul et al, 2011 ; Huynh and Marais, 2019 ; Fuad et al, 2020 ).…”