Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides

Lázár, Viktória and Martins, Ana and Spohn, Réka and Daruka, Lejla and Grézal, Gábor and Fekete, Gergely and Számel, Mónika and Jangir, Pramod Kumar and Kintses, Bálint and Csörgő, Bálint and Nyerges, Ákos and Györkei, Ádám and Kincses, András and Dér, András and Walter, Fruzsina and Deli, Mária Anna and Zsoldiné Urbán, Edit and Hegedűs, Zoltán and Méhi, Orsolya Katinka and Bálint, Balázs and Nagy, István and Martinek, Tamás and Papp, Balázs and Pál, Csaba (2018) Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides. NATURE MICROBIOLOGY, 3 (6). pp. 718-731. ISSN 2058-5276

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Abstract

Antimicrobial peptides are promising alternative antimicrobial agents. However, little is known about whether resistance to small-molecule antibiotics leads to cross-resistance (decreased sensitivity) or collateral sensitivity (increased sensitivity) to antimicrobial peptides. We systematically addressed this question by studying the susceptibilities of a comprehensive set of 60 antibiotic-resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic-resistant bacteria show a high frequency of collateral sensitivity to antimicrobial peptides, whereas cross-resistance is relatively rare. We identify clinically relevant multidrug-resistance mutations that increase bacterial sensitivity to antimicrobial peptides. Collateral sensitivity in multidrug-resistant bacteria arises partly through regulatory changes shaping the lipopolysaccharide composition of the bacterial outer membrane. These advances allow the identification of antimicrobial peptide-antibiotic combinations that enhance antibiotic activity against multidrug-resistant bacteria and slow down de novo evolution of resistance. In particular, when co-administered as an adjuvant, the antimicrobial peptide glycine-leucine-amide caused up to 30-fold decrease in the antibiotic resistance level of resistant bacteria. Our work provides guidelines for the development of efficient peptide-based therapies of antibiotic-resistant infections.

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