Dual-Uptake Mode of the Antibiotic Phazolicin Prevents Resistance Acquisition by Gram-Negative Bacteria
Dmitrii Y. Travin, Romain Jouan, Armelle Vigouroux, Satomi Inaba‐Inoue, Joy Lachat, Fazal Haq, Tatiana Timchenko, Dmitry Sutormin, Svetlana Dubiley, Konstantinos Beis, Solange Moréra, Konstantin Severinov, Peter Mergaert
Abstract
Many bacteria produce antimicrobial peptides to eliminate competitors and create an exclusive niche. These peptides act either by membrane disruption or by inhibiting essential intracellular processes. The Achilles' heel of the latter type of antimicrobials is their dependence on transporters to enter susceptible cells. Transporter inactivation results in resistance. Here, we show that a rhizobial ribosome-targeting peptide, phazolicin (PHZ), uses two different transporters, BacA and YejABEF, to enter the cells of a symbiotic bacterium, Sinorhizobium meliloti. This dual-entry mode dramatically reduces the probability of the appearance of PHZ-resistant mutants. Since these transporters are also crucial for S. meliloti symbiotic associations with host plants, their inactivation in natural settings is strongly disfavored, making PHZ an attractive lead for the development of biocontrol agents for agriculture.