Amphiphilic cationic macromolecule potentiates tetracycline against multi-drug resistant Gram-negative bacteria
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Bull Mater Sci (2020)43:311 https://doi.org/10.1007/s12034-020-02284-3
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Amphiphilic cationic macromolecule potentiates tetracycline against multi-drug resistant Gram-negative bacteria SUDIP MUKHERJEE, SREYAN GHOSH and JAYANTA HALDAR* Antimicrobial Research Laboratory, New Chemistry Unit and School of Advanced Materials, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru 560064, India *Author for correspondence ([email protected]) MS received 25 February 2020; accepted 17 July 2020 Abstract. Drug resistance in Gram-negative bacteria is leading the public health towards a global crisis and is further compounded by the dearth in developing new antibiotics to treat these pathogens over the last five decades. Among the various proposed mechanisms of resistance development, exclusion of drug from bacterial cells by efflux pumps act as an efficient machinery expelling a broad range of antibiotics thereby lowering intracellular antibiotic concentration and rendering the available antibiotics obsolete. Among various classes of antibiotics, tetracyclines suffer resistance through efflux mechanism. Currently, resurrecting the obsolete antibiotic by using the non-antibiotic drugs/adjuvants has become one of the key successes to tackle the multi-drug resistant (MDR) Gram-negative bacterial infections. Herein, we report the sensitization of tetracycline with the help of a membrane active macromolecule, ACM-AHex against the resistant Gram-negative pathogens. ACM-AHex was found to exert its antibacterial action by depolarizing the membrane potential. Thereby increasing the accumulation of tetracycline in Gram-negative pathogens. The combination of the compound with tetracycline has demonstrated 4–128-fold potentiation in the antibacterial activity of the antibiotic. Overall, these in vitro studies have demonstrated immense potential of this combination to be further developed as therapeutic agents to treat Gram-negative bacterial infections. Keywords.
1.
Antimicrobial resistance; adjuvants; combination therapy; tetracycline; antimicrobial macromolecule.
Introduction
Global emergence of drug resistant Gram-negative pathogens has turned out to be a challenging threat jeopardizing the public health worldwide and without necessary action being taken, a pre-antibiotic era is inevitable [1,2]. Despite the relentless efforts from various research groups for development of therapeutic regimen against Gram-negative bacterial infections, there is stagnation in the discovery, development and approval of novel antibiotics coupled with an increasing morbidity and mortality associated with such notorious infections [3,4]. Among the infamous Gramnegative pathogens, A. baumannii, P. aeruginosa and Enterobacteriaceae species (K. pneumoniae, E. coli), have been prioritized as top critical pathogens by the World Health Organization (WHO), owing to their biofilm-forming capability and complex strategies of resistance development [5,6]. Bacteria can develop resistance again
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