Pai, S. V. | Search bioRxiv

bioRxiv2026

SOS-mediated prophage induction constrains resistance evolution to DNA-damaging antibiotics

Most naturally occurring bacteria are lysogens, encoding one or more temperate phages (prophages) integrated into their genome. As prophages are induced by the bacterial SOS response, DNA-damaging antibiotics can trigger SOS-mediated prophage induction, where prophages undergo lytic replication and lyse their host, even at sub-inhibitory concentrations. This prophage-antibiotic synergy therefore sensitizes lysogenic hosts to DNA-damaging antibiotics. However, the mechanism by which prophage-induced sensitization affects the evolution of resistance against these agents is unclear. Here we show that ciprofloxacin-resistant lysogens arise less frequently but exhibit higher levels of resistance following selection. Whole-genome sequencing showed that increased lysogen resistance arose from selection towards mutations in drug targets, efflux pathways, and stress response regulators that reduce antibiotic efficacy or alter SOS induction. Consistent with this result, resistant lysogens exhibited a dampened SOS response, suggesting that prophage induction imposes an additional selective filter on their hosts by eliminating mutants that experience sufficient DNA damage to activate the SOS response. By contrast, prophage carriage had no effect on sensitivity or resistance evolution for antibiotics where DNA damage occurs downstream of the primary mechanism of action. Together, these findings indicate that prophage induction acts as an evolutionary bottleneck that restricts many resistance trajectories while favoring the emergence of rarer, large-effect mutations, potentially accelerating the evolution of high-level resistance.

microbiology↗

bioRxiv2025

Sex decreases the pleiotropic costs of local adaptation

Understanding the evolutionary mechanisms that maintain sex throughout nature despite its substantial direct costs is a longstanding challenge in biology. Previous work has shown that sexual recombination provides a key advantage in speeding adaptation, in part by separating beneficial mutations from deleterious hitchhikers. However, these earlier studies have focused on the effects of sex in a constant environment. Here, we show that recombination also provides a key advantage in fluctuating conditions, promoting the evolution of generalist phenotypes by reducing the pleiotropic costs of local adaptation. Using laboratory evolution in S. cerevisiae as a model system, we show that hitchhiking genetic load leads to pleiotropic costs and hence specialization in response to local adaptation in asexual but not in sexual lineages. This provides the first direct evidence that sex can be maintained over longer evolutionary timescales because it enables lineages to persist in the face of environmental change.

evolutionary biology↗