A Glycosylated Cationic Block Poly(β‐peptide) Reverses Intrinsic Antibiotic Resistance in All ESKAPE Gram‐Negative Bacteria
Zhangyong Si, Hui Wen Lim, Moon Y. F. Tay, Yu Du, Lin Ruan, Haofeng Qiu, Rubí Zamudio-Vázquez, Sheethal Reghu, Yahua Chen, Wen Shuo Tiong, Kalisvar Marimuthu, Partha Pratim De, Oon Tek Ng, Yabin Zhu, Yunn‐Hwen Gan, Yonggui Robin, Hongwei Duan, Guillermo C. Bazan, E. Peter Greenberg, Mary B. Chan‐Park, Kévin Pethe
Abstract
Carbapenem-resistant Gram-negative bacteria (GNB) are heading the list of pathogens for which antibiotics are the most critically needed. Many antibiotics are either unable to penetrate the outer-membrane or are excluded by efflux mechanisms. Here, we report a cationic block β-peptide (PAS8-b-PDM12) that reverses intrinsic antibiotic resistance in GNB by two distinct mechanisms of action. PAS8-b-PDM12 does not only compromise the integrity of the bacterial outer-membrane, it also deactivates efflux pump systems by dissipating the transmembrane electrochemical potential. As a result, PAS8-b-PDM12 sensitizes carbapenem- and colistin-resistant GNB to multiple antibiotics in vitro and in vivo. The β-peptide allows the perfect alternation of cationic versus hydrophobic side chains, representing a significant improvement over previous antimicrobial α-peptides sensitizing agents. Together, our results indicate that it is technically possible for a single adjuvant to reverse innate antibiotic resistance in all pathogenic GNB of the ESKAPE group, including those resistant to last resort antibiotics.