Chemical-genetic profiling to investigate cross-resistance and collateral sensitivity between antimicrobial peptides

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Abstract in foreign language

Antimicrobial peptides (AMPs) are crucial components of the host immune system and have been proposed as promising novel anti-infectives. However, there is a serious concern that therapeutic application of AMPs would drive bacterial cross-resistance to our own immunity peptides. Our knowledge of cross-resistance between AMPs remains extremely limited. To address this gap, we used chemical-genetic approaches to uncover the resistance determinants of E. coli against 15 different AMPs. This comprehensive compendium revealed multiple and functionally diverse genes that modulate bacterial susceptibility to different AMPs. Interestingly, AMPs differ considerably in their resistance determinants, and resistance-enhancing genes overlap only to a limited extent between AMPs. As a consequence, collateral sensitivity effects were common: numerous genes decreased susceptibility to one AMP while simultaneously sensitized to others. Finally, by integrating laboratory evolution approach, we showed that our chemical-genetic map informed on the cross-resistance interactions between AMPs. In the future, the chemical-genetic map could inform efforts to avoid cross-resistance between therapeutic and human host AMPs.

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