History of antibiotic adaptation influences microbial evolutionary dynamics during subsequent treatment

Abstract

Antibiotic regimens often include the sequential changing of drugs to limit the development and evolution of resistance of bacterial pathogens. It remains unclear how history of adaptation to one antibiotic can influence the resistance profiles when bacteria subsequently adapt to a different antibiotic. Here, we experimentally evolved Pseudomonas aeruginosa to six 2-drug sequences. We observed drug order–specific effects, whereby adaptation to the first drug can limit the rate of subsequent adaptation to the second drug, adaptation to the second drug can restore susceptibility to the first drug, or final resistance levels depend on the order of the 2-drug sequence. These findings demonstrate how resistance not only depends on the current drug regimen but also the history of past regimens. These order-specific effects may allow for rational forecasting of the evolutionary dynamics of bacteria given knowledge of past adaptations and provide support for the need to consider the history of past drug exposure when designing strategies to mitigate resistance and combat bacterial infections.

Mutation-Driven Evolution of Pseudomonas aeruginosa in the Presence of either Ceftazidime or Ceftazidime-Avibactam

“…In both cases, the first event in the evolution seems to be the deletion of large regions of the P. aeruginosa chromosome that comprise, among several other genes, hmgA, galU, and mexXY. A similar situation has been previously reported in other P. aeruginosa experimental evolution assays in the presence of ␤-lactams, such as piperacillin (41) and meropenem (45). Additionally, pyomelaninproducing mutants are regularly isolated from infections; up to 13% of CF patients harbor pyomelanin-producing mutants (52), likely because the production of pyomelanin increases resistance to oxidative stress and persistence in chronic lung infections (21).…”

“…Moreover, pepA mutants are selected in the presence of aztreonam (27). SpoT has been related to piperacillin resistance (41), while DnaJ, a chaperone protein, and FlgF, a flagellar basal body rod protein (42), have been reported to modify the susceptibility of E. coli to a range of antibiotics when they are inactivated (35).…”

Modeling the interplay between plastic tradeoffs and evolution in changing environments

“…We hope the model presented here will help develop null-model phenomenological expectations, against which experimental (and genealogical) results can be compared (e.g. [21]).…”

“…Furthermore, tradeoffs will depend on evolutionary history and themselves evolve [13][14][15][16][17][18]. In laboratory experiments, adapting bacteria to one task can both hinder and improve their performance at another, depending on the experimental protocol, the studied strain, and the exact nature of the tasks, as well as history of prior exposure [19][20][21]. Some phenomena appear non-intuitive and surprising, for instance, even very weak levels of an antibiotic can induce resistance to much higher levels [22,23].…”

Evolution of the Pseudomonas aeruginosa Aminoglycoside Mutational Resistome In Vitro and in the Cystic Fibrosis Setting

“…Whereas resistance to these agents in acute infections is mainly attributed to the production of aminoglycoside-modifying enzymes or 16S rRNA methyltransferases, resistance development in the chronic infection setting has been linked to the selection of chromosomal mutations that lead to enhanced membrane impermeability or MexXY-OprM efflux pump overexpression (12)(13)(14). However, high-level resistance development likely requires the accumulation of different resistance mechanisms, and, although recent reports suggest the involvement of additional chromosomal mutations (15)(16)(17)(18)(19)(20), there are still important knowledge gaps in this field. Thus, the aim of this work was to analyze the in vitro evolution of the aminoglycoside mutational resistome of P. aeruginosa and to correlate the documented mutations with those observed in vivo during the course of CF chronic respiratory infection.…”