Aryl-alkyl-lysines: Membrane-Active Small Molecules Active against Murine Model of Burn Infection.
Infections caused by drug-resistant Gram-negative pathogens continue to be significant contributors to human morbidity. The recent advent of New Delhi metallo-β-lactamase-1 (blaNDM-1) producing pathogens, against which few drugs remain active, has aggravated the problem even further. This paper shows that aryl-alkyl-lysines, membrane-active small molecules, are effective in treating infections caused by Gram-negative pathogens. One of the compounds of the study was effective in killing planktonic cells as well as dispersing biofilms of Gram-negative pathogens. The compound was extremely effective in disrupting preformed biofilms and did not select resistant bacteria in multiple passages. The compound retained activity in different physiological conditions and did not induce any toxic effect in female Balb/c mice until concentrations of 17.5 mg/kg. In a murine model of Acinetobacter baumannii burn infection, the compound was able to bring the bacterial burden down significantly upon topical application for 7 days.
Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bengaluru 560064, Karnataka, India.
Chandradhish
C
Ghosh
Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bengaluru 560064, Karnataka, India.
Goutham B
GB
Manjunath
Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bengaluru 560064, Karnataka, India.
Mohini M
MM
Konai
Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bengaluru 560064, Karnataka, India.
Divakara S S M
DS
Uppu
National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI) Ramagondanahalli , Yelahanka, Bengaluru 560064, Karnataka, India.
Krishnamoorthy
K
Paramanandham
National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI) Ramagondanahalli , Yelahanka, Bengaluru 560064, Karnataka, India.
Bibek R
BR
Shome
Department of Neuromicrobiology, National Institute of Mental Health and Neurosciences , Hosur Road, Bengaluru 560029, Karnataka, India.
Raju
R
Ravikumar
Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bengaluru 560064, Karnataka, India.
Jayanta
J
Haldar
D040981:Acinetobacter baumannii / Q000187:drug effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D002056:Burns / Q000382:microbiology*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D005260:Female; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D014946:Wound Infection / Q000382:microbiology*; D001618:beta-Lactamases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D008239:Lysine
Gram-negative; antibiotics; antimicrobial peptides; antimicrobial resistance; biofilm; burn infection; persisters