Editors' ChoiceTuberculosis

The path of least antibiotic resistance

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Science Translational Medicine  10 May 2017:
Vol. 9, Issue 389, eaan3778
DOI: 10.1126/scitranslmed.aan3778

Abstract

Antibiotic combination therapy alters Mycobacterium tuberculosis population dynamics in the human host.

Antimicrobial resistance is a rising global health threat. Combination therapy is a powerful tool to combat resistance and is implemented by using multiple antibiotics with differing mechanisms of action concurrently. To develop resistance, cells must overcome the substantial pressure conferred by these differing mechanisms of action. For tuberculosis (TB), standard therapy is a four-antibiotic regimen administered over 6 months. When applied correctly, combination therapy leads to low rates of TB relapse and acquired resistance.

The mutations that underlie TB drug resistance potentiated by treatment failure have been well studied. However, Trauner et al. sought to understand the processes that shape successful combination treatment of TB by examining Mycobacterium tuberculosis (mTB) population dynamics within the human host. They collected sequential sputum samples over 8 weeks from 12 participants, eight with drug-susceptible TB and four with drug resistance. They performed whole genome sequencing on the isolates and examined the dynamics of the identified single nucleotide polymorphisms (SNPs) over time and in relation to treatment efficacy.

The authors found that mTB isolates demonstrate immense genetic heterogeneity, which is mostly due to the contributions of rare variants present only in one of multiple concurrently collected samples at single time points. They concluded that there is greater genetic instability of mTB than previously thought, with continuous turnover of genetic variants within a host. In effectively treated participants, nonsynonymous (amino acid–altering) SNPs were less likely to remain over time than synonymous (non-amino acid–altering) SNPs, a finding not seen in inadequately treated participants, in whom there was also excessive mutation accumulation in known drug target genes. They concluded that successful therapy leads to purifying selection against deleterious mutations. With unsuccessful treatment, drug pressure is alleviated, allowing for emergence of resistance. Importantly, the researchers did not find an accumulation of pathoadaptive mutations amongst successfully treated participants, as is seen with many opportunistic infections. However, the broad sequencing approach may have limited that analysis.

Given the public health impact of antimicrobial resistance, understanding the mechanisms that lead to the successful avoidance of resistance is essential. Trauner and colleagues get us one step closer by focusing on the population dynamics of mTB amongst patients who do and do not develop resistance.

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