The Essential Role of Hypermutation in Rapid Adaptation to Antibiotic Stress

Abstract

A common outcome of antibiotic exposure in patients and in vitro is the evolution of a hypermutator phenotype that enables rapid adaptation by pathogens. While hypermutation is a robust mechanism for rapid adaptation, it requires trade-offs between the adaptive mutations and the more common "hitchhiker" mutations that accumulate from the increased mutation rate. Using quantitative experimental evolution, we examined the role of hypermutation in driving the adaptation of Pseudomonas aeruginosa to colistin. Metagenomic deep sequencing revealed 2,657 mutations at Ն5% frequency in 1,197 genes and 761 mutations in 29 endpoint isolates. By combining genomic information, phylogenetic analyses, and statistical tests, we showed that evolutionary trajectories leading to resistance could be reliably discerned. In addition to known alleles such as pmrB, hypermutation allowed identification of additional adaptive alleles with epistatic relationships. Although hypermutation provided a short-term fitness benefit, it was detrimental to overall fitness. Alarmingly, a small fraction of the colistin-adapted population remained colistin susceptible and escaped hypermutation. In a clinical population, such cells could play a role in reestablishing infection upon withdrawal of colistin. We present here a framework for evaluating the complex evolutionary trajectories of hypermutators that applies to both current and emerging pathogen populations.

<p>Small Molecule Adjuvants Potentiate Colistin Activity and Attenuate Resistance Development in <em>Escherichia coli</em> by Affecting <em>pmr</em>AB System</p>

“…It is likely that these mutations might just represent adaptive mutations induced to compensate colistin stress or secondary to pmrAB mutations and induced lipid A modifications. The induction of prophage to adapt antibiotic stress was observed when P. aeruginosa was exposed to colistin, 63 which can support our finding. Further investigation is necessary to understand the precise role of these mutations in colistin resistance which can help in understanding molecular sequelae associated with colistin resistance.…”

Adaptations Accumulated under Prolonged Resource Exhaustion Are Highly Transient

“…Our results indicate that if resistance is not fixed, the dynamics of resistance maintenance may be highly affected by costs associated with antibiotic resistance adaptation. Furthermore, studies have shown that mutators may often contribute to the emergence of clinical antibiotic resistance (32,33). Our results demonstrate that such mutators may be much more likely to lose even fixed costly adaptations through reversion mutations, rather than maintain them through compensation.…”

Broad and Dynamic Diversification of Infectious Hepatitis C Virus in a Cell Culture Environment

“…According to our evidence and models, broad diversification should operate in biological systems characterized by high effective population sizes and elevated mutation rates, and it implies that environmental constancy does not impair prospects for adaptation. Such requirements are not exclusive to viruses; they are, at least, also fulfilled by cancer cells in large tumors (67), as well as in large microbial populations, in particular by their mutator versions (68). For multicellular organisms with their usual population sizes, low mutation rates, and characteristic functional constraints, broad diversification is not attainable.…”