title: Membrane-active macromolecules resensitize NDM-1 gram-negative clinical isolates to tetracycline antibiotics.
abstract: Gram-negative 'superbugs' such as New Delhi metallo-beta-lactamase-1 (blaNDM-1) producing pathogens have become world's major public health threats. Development of molecular strategies that can rehabilitate the 'old antibiotics' and halt the antibiotic resistance is a promising approach to target them. We report membrane-active macromolecules (MAMs) that restore the antibacterial efficacy (enhancement by >80-1250 fold) of tetracycline antibiotics towards blaNDM-1 Klebsiella pneumonia and blaNDM-1 Escherichia coli clinical isolates. Organismic studies showed that bacteria had an increased and faster uptake of tetracycline in the presence of MAMs which is attributed to the mechanism of re-sensitization. Moreover, bacteria did not develop resistance to MAMs and MAMs stalled the development of bacterial resistance to tetracycline. MAMs displayed membrane-active properties such as dissipation of membrane potential and membrane-permeabilization that enabled higher uptake of tetracycline in bacteria. In-vivo toxicity studies displayed good safety profiles and preliminary in-vivo antibacterial efficacy studies showed that mice treated with MAMs in combination with antibiotics had significantly decreased bacterial burden compared to the untreated mice. This report of re-instating the efficacy of the antibiotics towards blaNDM-1 pathogens using membrane-active molecules advocates their potential for synergistic co-delivery of antibiotics to combat Gram-negative superbugs.
authors: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, 560064, India.
authors: Divakara S S M
authors: DS
authors: Uppu
authors: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, 560064, India.
authors: Goutham B
authors: GB
authors: Manjunath
authors: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, 560064, India.
authors: Venkateswarlu
authors: V
authors: Yarlagadda
authors: Department of Neuromicrobiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
authors: Jyothi E
authors: JE
authors: Kaviyil
authors: Department of Neuromicrobiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
authors: Raju
authors: R
authors: Ravikumar
authors: National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Hebbal, Bengaluru, 560024, Karnataka, India.
authors: Krishnamoorthy
authors: K
authors: Paramanandham
authors: National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Hebbal, Bengaluru, 560024, Karnataka, India.
authors: Bibek R
authors: BR
authors: Shome
authors: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bangalore, 560064, India.
authors: Jayanta
authors: J
authors: Haldar
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008301:Maleimides / Q000008:administration & dosage* / Q000737:chemistry; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D013752:Tetracycline / Q000008:administration & dosage*; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D008301:Maleimides; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D013752:Tetracycline