  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
{\beta}-lactamase (blaTEM) varied greatly among 15 different {\beta}-lactam
antibiotics. We captured those differences by characterizing complete adaptive
landscapes for the resistance alleles blaTEM-50 and blaTEM-85, each of which
differs from its ancestor blaTEM-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.
