Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance

Abstract

<jats:p>Bacteria frequently encounter selection by both antibiotics and lytic bacteriophages. However, the evolutionary interactions between antibiotics and phages remain unclear, in particular, whether and when phages can drive evolutionary trade-offs with antibiotic resistance. Here, we describe<jats:italic>Escherichia coli</jats:italic>phage U136B, showing it relies on two host factors involved in different antibiotic resistance mechanisms: 1) the efflux pump protein TolC and 2) the structural barrier molecule lipopolysaccharide (LPS). Since TolC and LPS contribute to antibiotic resistance, phage U136B should select for their loss or modification, thereby driving a trade-off between phage resistance and either of the antibiotic resistance mechanisms. To test this hypothesis, we used fluctuation experiments and experimental evolution to obtain phage-resistant mutants. Using these mutants, we compared the accessibility of specific mutations (revealed in the fluctuation experiments) to their actual success during ecological competition and coevolution (revealed in the evolution experiments). Both<jats:italic>tolC</jats:italic>and LPS-related mutants arise readily during fluctuation assays, with<jats:italic>tolC</jats:italic>mutations becoming more common during the evolution experiments. In support of the trade-off hypothesis, phage resistance via<jats:italic>tolC</jats:italic>mutations occurs with a corresponding reduction in antibiotic resistance in many cases. However, contrary to the hypothesis, some phage resistance mutations pleiotropically confer increased antibiotic resistance. We discuss the molecular mechanisms underlying this surprising pleiotropic result, consideration for applied phage biology, and the importance of ecology in evolution of phage resistance. We envision that phages may be useful for the reversal of antibiotic resistance, but such applications will need to account for unexpected pleiotropy and evolutionary context.</jats:p>

Dead cells release a ‘necrosignal’ that activates antibiotic survival pathways in bacterial swarms

“…We next sought to identify residues critical for the response in both AcrA and TolC. For TolC, we took advantage of reports that TolC serves as a receptor for certain colicins 25 and bacteriophages 26,27 , using residues important for phage binding 26 as a guide for our mutagenesis (Fig. 4b).…”

Transcriptomic determinants of the response of ST-111 Pseudomonas aeruginosa AG1 to ciprofloxacin identified by a top-down systems biology approach

“…Phage induction is known to be modulated upon stress conditions, including the SOS response 88 . As found recently for some antimicrobials, phage activity is product of pleiotropic regulation 89 . In the presence of sub-lethal concentrations of certain antibiotics, phages have been observed to be induced or to form larger phage plaques 88,90 .…”

Tackling Intrinsic Antibiotic Resistance in Serratia marcescens with a Combination of Ampicillin/Sulbactam and Phage SALSA

“…Conversely, at least in our laboratory, bacterial re-growth has been less frequently observed with phages applied against other opportunistic pathogens, such as Acinetobacter baumannii [ 7 ], Pseudomonas aeruginosa [ 49 ] or Staphylococcus aureus (unpublished data). It appears that Enterobacteriaceae are particularly well-“armed” against phages [ 50 ]. Therapeutic success may therefore depend on the use of phage cocktails which prevents or at least retards phage resistance development.…”