About AMR: Prior adaptation to antibiotics impacts subsequent development of antibiotic resistance

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Two recent studies have highlighted how prior antibiotic exposure can influence the later occurrence of resistance to other antibiotics in Pseudomonas aeruginosa. Both studies applied an experimental evolution approach to adapt P. aeruginosa to one antibiotic and then investigated the consequence on resistance to additional antibiotics, revealing collateral effects that could inform cycling or combination therapy strategies and help counter the development of multidrug-resistant strains.

The acquisition of spontaneous antibiotic-resistance mutations can have unintended consequences on bacterial fitness in the presence of other antibiotics. In some cases, adaptive mutations conferring resistance to one class of antibiotic can also confer cross-resistance to another class. In other cases, adaptive mutations can increase the susceptibility to another antibiotic. Both cases are exploited in a clinical setting with combinatory therapy or cycling therapy to reduce the occurrence of multidrug-resistant strains, yet the optimal employment of these strategies and underlying mechanisms remain incompletely understood.

Two recent studies have investigated these collateral effects in P. aeruginosa. In a study by Barbosa and colleagues in Molecular Biology and Evolution, the authors adapted P. aeruginosa to 20 different antibiotics and then examined the collateral effects on resistance to other antibiotics.

They discovered that P. aeruginosa evolved diverse resistance mechanisms to a single antibiotic, including mutations in the direct target of the antibiotics, as well as mutations in regulatory systems, efflux pumps and even genes with no previous implication in antibiotic resistance. When they assessed how these mutations influenced the susceptibility of P. aeruginosa to a second antibiotic, they found that the diversity of adaptive mutations equated to pleiotropic effects on the occurrence of resistance to subsequent antibiotics – with some promoting cross-resistance and others promoting collateral sensitivity.

The authors next investigated whether a specific set of mutations was correlated with either cross-resistance or collateral sensitivity. Although there was no association between specific adaptive mutations and cross-resistance, they did observe associations between certain adaptive mutations and collateral sensitivity.

For example, aminoglycoside-adapted P. aeruginosa with mutations in either pmrB, a sensor kinase that responds and regulates adaptation to cationic antimicrobial peptides, or mexZ, a transcriptional repressor that controls expression of an efflux system, were associated with collateral sensitivity to penicillins. Penicillin-adapted P. aeruginosa with mutations in nalC, a transcriptional repressor of another efflux system, were associated with collateral sensitivity to aminoglycosides. Thus, the study revealed two important categories of genes involved in collateral sensitivity in P. aeruginosa – efflux system regulators and two-component regulatory systems.

In a second study conducted by Yen and colleagues, published in PLoS Biology, the authors extended the adaptation experiments further. Following the first round of adaptation of P. aeruginosa to one antibiotic, they performed a subsequent round of adaptation to a second antibiotic. The additional round of experimental evolution allowed the group to question whether adaptation to one antibiotic could potentiate or constrain the development of resistance to a second class of antibiotic, and whether the adaptation to the second antibiotic resensitized P. aeruginosa to the first.

This approach revealed that penicillin-adaptation constrained the extent to which P. aeruginosa could develop resistance to aminoglycosides, fluoroquinolone-adaptation potentiated the development of penicillin and aminoglycoside resistance, and aminoglycoside-adaptation constrained development of fluoroquinolone resistance. These data indicate that not only does prior exposure have immediate consequences on antibiotic susceptibility, but also on the long-term evolutionary dynamics of P. aeruginosa upon subsequent antibiotic exposure.

When the authors examined whether adaptation to the second class resensitized P. aeruginosa resistance to the first antibiotic, they observed that adaptation to fluoroquinolones re-sensitized P. aeruginosa to penicillins, and adaptation to penicillins and aminoglycosides resensitized P. aeruginosa to fluoroquinolones.

Altogether, these studies reveal important mechanisms involved in the collateral effects of adaptation to antibiotic exposure in P. aeruginosa and could inform the order of antibiotics selected for use in cycling therapies to help minimize the occurrence of multidrug-resistant strains.

Sources:
  1. Yen P, Papin JA. History of antibiotic adaptation influences microbial evolutionary dynamics during subsequent treatment. PLoS Biol 15(8): e2001586 (2017)
  2. Barbosa C, Tresbosc V, Kemmer C. et al., Alternative evolutionary paths to bacterial antibiotic resistance cause distinct collateral effects. Mol Bio and Evol 34(9):2229-2244 (2017)
About the author

Julie Kaiser is a Ph.D. candidate in Microbiology at the University of Western Ontario in London, Canada. Her research interests range from the impact of microbial communities on human health, to the molecular basis of drug-resistant bacterial infections. Julie enjoys sharing her love for the microbial world through science communication and is the author of Microbiology for Dummies. Follow her on twitter at @jukais.

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