PT  - JOURNAL ARTICLE
AU  - Nagarajan, Deepesh
AU  - Roy, Natasha
AU  - Kulkarni, Omkar
AU  - Nanajkar, Neha
AU  - Datey, Akshay
AU  - Ravichandran, Sathyabaarathi
AU  - Thakur, Chandrani
AU  - T., Sandeep
AU  - Aprameya, Indumathi V.
AU  - Sarma, Siddhartha P.
AU  - Chakravortty, Dipshikha
AU  - Chandra, Nagasuma
TI  - Ω76: A designed antimicrobial peptide to combat carbapenem- and tigecycline-resistant <em>Acinetobacter baumannii</em>
AID  - 10.1126/sciadv.aax1946
DP  - 2019 Jul 01
TA  - Science Advances
PG  - eaax1946
VI  - 5
IP  - 7
4099  - http://advances.sciencemag.org/content/5/7/eaax1946.short
4100  - http://advances.sciencemag.org/content/5/7/eaax1946.full
SO  - Sci Adv2019 Jul 01; 5
AB  - 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 (Ω76) displayed high efficacy against carbapenem and tigecycline-resistant Acinetobacter baumannii in mice. Mice treated with repeated sublethal doses of Ω76 displayed no signs of chronic toxicity. Sublethal Ω76 doses co-administered alongside sublethal colistin doses displayed no additive toxicity. These results indicate that Ω76 can potentially supplement or replace colistin, especially where nephrotoxicity is a concern. To our knowledge, no other existing antibiotics occupy this clinical niche. Mechanistically, Ω76 adopts an α-helical structure in membranes, causing rapid membrane disruption, leakage, and bacterial death.