Designing Antibiotic Cycling Strategies by Determining and Understanding Local Adaptive Landscapes

Abstract

The evolution of antibiotic resistance among bacteria threatens our continued ability to treat infectious diseases. The need for sustainable strategies to cure bacterial infections has never been greater. So far, all attempts to restore susceptibility after resistance has arisen have been unsuccessful, including restrictions on prescribing [1] and antibiotic cycling [2], [3]. Part of the problem may be that those efforts have implemented different classes of unrelated antibiotics, and relied on removal of resistance by random loss of resistance genes from bacterial populations (drift). Here, we show that alternating structurally similar antibiotics can restore susceptibility to antibiotics after resistance has evolved. We found that the resistance phenotypes conferred by variant alleles of the resistance gene encoding the TEM β-lactamase (bla TEM) varied greatly among 15 different β-lactam antibiotics. We captured those differences by characterizing complete adaptive landscapes for the resistance alleles bla TEM-50 and bla TEM-85, each of which differs from its ancestor bla TEM-1 by four mutations. We identified pathways through those landscapes where selection for increased resistance moved in a repeating cycle among a limited set of alleles as antibiotics were alternated. Our results showed that susceptibility to antibiotics can be sustainably renewed by cycling structurally similar antibiotics. We anticipate that these results may provide a conceptual framework for managing antibiotic resistance. This approach may also guide sustainable cycling of the drugs used to treat malaria and HIV.

Strategies to Minimize Antibiotic Resistance

“…In fact, recent reports show that improved cycling strategy can reduce antibiotic resistance [111,112,113,114,115,116]. Periodic Antibiotic Monitoring and Supervision (PAMS), in particular, is a novel strategy that is based on antibiotic heterogeneity [99,101,116].…”

Effect of Host Species on Topography of the Fitness Landscape for a Plant RNA Virus

“…Understanding the roles that environmental changes and landscape topology have in the number and nature of adaptive pathways would allow prediction of the potential avenues of future evolution. Despite this importance, how environmental heterogeneity affects the topography of fitness landscapes is still poorly understood, and only a few recent studies have started to tackle this problem, mostly in the context of the evolution of antibiotic resistances (20)(21)(22)(23) or during experimental adaptation of Escherichia coli to an artificial glucose-limited environment (24).…”

Strategies to avoid treatment-induced lineage crisis in advanced prostate cancer

“…Various elegant studies have resulted in the development of mathematical models that predict the optimal sequence of drugs with a maximum lethal effect in a scenario in which each individual drug would likely fail 146 . Mathematical algorithms that model microbial fitness have also been used to consider how antibiotic cycling can be used to avoid the continued selective pressure that would lead to the selection and expansion of a population with a resistant phenotype 150 . Such drug-cycling strategies have proven to be successful for the treatment of infections with bacteria and eukariotic parasites 151–153 .…”