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-Vazquez; Sheethal Reghu; Yahua Chen; Wen Shuo Tiong; Kalisvar Marimuthu; Partha Pratim De; Oon Tek Ng; Yabin Zhu; Yunn-Hwen Gan; Yonggui Robin Chi; Hongwei Duan; Guillermo C Bazan; E Peter Greenberg; Mary B Chan-Park; Kevin Pethe

doi:10.1002/anie.201914304

A Glycosylated Cationic Block Poly(β-peptide) Reverses Intrinsic Antibiotic Resistance in All ESKAPE Gram-Negative Bacteria

Angew Chem Int Ed Engl. 2020 Apr 20;59(17):6819-6826. doi: 10.1002/anie.201914304. Epub 2020 Feb 19.

Authors

Zhangyong Si¹, Hui Wen Lim², Moon Y F Tay¹, Yu Du¹, Lin Ruan¹, Haofeng Qiu³, Rubí Zamudio-Vazquez¹, Sheethal Reghu¹, Yahua Chen⁴, Wen Shuo Tiong², Kalisvar Marimuthu^{5

6

7}, Partha Pratim De⁵, Oon Tek Ng^{2

5

7}, Yabin Zhu³, Yunn-Hwen Gan⁴, Yonggui Robin Chi⁸, Hongwei Duan¹, Guillermo C Bazan^{1

9}, E Peter Greenberg^{1

10}, Mary B Chan-Park^{1

2}, Kevin Pethe^{2

11}

Affiliations

¹ School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, 637459, Singapore.
² Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 636921, Singapore.
³ Medical School of Ningbo University, Ningbo University, Ningbo, 315211, China.
⁴ Department of Biochemistry, National University of Singapore, Singapore, 117596, Singapore.
⁵ Tan Tock Seng Hospital, Singapore, 308433, Singapore.
⁶ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
⁷ National Centre for Infectious Diseases, Singapore.
⁸ Division of Chemistry & Biological Chemistry, Nanyang Technological University, Singapore, 637371, Singapore.
⁹ Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106-9510, USA.
¹⁰ Department of Microbiology, University of Washington, Seattle, WA, 98195, USA.
¹¹ School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.

PMID: 32011781
DOI: 10.1002/anie.201914304

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.

Keywords: antimicrobial resistance; carbapenems; efflux pumps; medicinal chemistry; β-peptides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology*
Carbapenems / pharmacology
Drug Resistance, Multiple, Bacterial / drug effects
Glycosylation
Gram-Negative Bacteria / drug effects*
Microbial Sensitivity Tests
Peptides / chemistry*
Peptides / pharmacology*
Protein Conformation, beta-Strand

Substances

Anti-Bacterial Agents
Carbapenems
Peptides