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?76: A designed antimicrobial peptide to combat carbapenem- and tigecycline-resistant Acinetobacter baumannii.


ABSTRACT: Drug resistance is a public health concern that threatens to undermine decades of medical progress. ESKAPE pathogens cause most nosocomial infections, and are frequently resistant to carbapenem antibiotics, usually leaving tigecycline and colistin as the last treatment options. However, increasing tigecycline resistance and colistin's nephrotoxicity severely restrict use of these antibiotics. We have designed antimicrobial peptides using a maximum common subgraph approach. Our best peptide (?76) displayed high efficacy against carbapenem and tigecycline-resistant Acinetobacter baumannii in mice. Mice treated with repeated sublethal doses of ?76 displayed no signs of chronic toxicity. Sublethal ?76 doses co-administered alongside sublethal colistin doses displayed no additive toxicity. These results indicate that ?76 can potentially supplement or replace colistin, especially where nephrotoxicity is a concern. To our knowledge, no other existing antibiotics occupy this clinical niche. Mechanistically, ?76 adopts an ?-helical structure in membranes, causing rapid membrane disruption, leakage, and bacterial death.

SUBMITTER: Nagarajan D 

PROVIDER: S-EPMC6656545 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

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