An ultrashort antibacterial lipopeptide acts as an antibiotic adjuvant to combat multi-drug resistant Gram-negative pathogens Apurva Panjla 1 , Grace Kaul 2,4 , Manjulika Shukla 2 , Abdul Akhir 2 , Sarita Tripathi 3 , Ashish Arora 3,4 , Sidharth Chopra 2,4 , Sandeep Verma 1,5 1 Department of Chemistry, IIT Kanpur, India, 2 Division of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, India, 3 Biochemistry and Structural Biology Division, CSIR- Central Drug Research Institute, India, 4 Academy of Scientific and Innovative Research (AcSIR), India, 5 Mehta Family Center for Engineering in Medicine, Center for Nanoscience, India The decimated antibiotic pipeline against continually rising multi-drug resistant Gram-negative bacteria (MDR- GNB) necessitates alternative strategies to combat infections, especially by WHO-designated critical priority pathogens. 1 Here, we report an ultrashort cationic lipopeptide SVAP9I as a potent antibiotic and adjuvant that potentiates existing antibiotic classes towards GNBs (Figure 1). The lipidated tetrapeptide exhibited broad- spectrum activity against critical MDR GNBs with fast concentration-dependent bactericidal action at an MIC of 4 mg/L and no detectable resistance in E. coli . It showed similar activity against polymyxin B-resistant E. coli and a post-antibiotic effect of ~4 h. SVAP9I targeted the bacterial membranes by predominantly binding to LPS in the outer membrane and phospholipids cardiolipin and phosphatidylglycerol prevalent in the inner membrane of E. coli . Membrane damage resulted in ROS generation, depleted intracellular ATP concentration, and a concomitant increase in extracellular ATP in E. coli, leading to cell death. At sub-inhibitory concentrations, it served as a potent permeabilizing agent for multiple GNBs including carbapenem-resistant A. baumannii (CRAB), a WHO critical priority pathogen. In murine in vivo model of thigh infection, SVAP9I and rifampicin synergized to express excellent antibacterial efficacy against MDR-CRAB outcompeting polymyxin B. Taken together, SVAP9I's distinct membrane-targeting broad-spectrum action against multiple MDR GNBs, lack of resistance and strong in vivo potency in combination suggest its potential as a novel antibiotic adjuvant for the treatment of serious MDR-GNB infections.
Figure 1. Schematic illustration of membrane disruption caused by SVAP9I resulting in potentiation of antibiotics towards MDR- GNB, leading to bacterial cell death. References 1. Venkatesan P. WHO 2020 report on the antibacterial production and development pipeline. Lancet Microbe 2021;2:e239. https://doi.org/10.1016/S2666-5247(21)00124-5.
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