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Discovery and development of new antimicrobial compounds against gram-negative bacteria resistant to carbapenems and cephalosporins

Abstract

One of the major concerns regarding human bacterial infections nowadays is the escalating development of antimicrobial resistance (AMR) that results primarily from the indiscriminate use of antibiotics, both in the clinic and agriculture. Despite all the advances in medicine since the discovery of penicillin, AMR has become one of the major public health problems in the world. This scenario has led the World Health Organization to launch recently a global AMR surveillance system to monitor the prevalence and advance of AMR cases around the globe and to provide reliable AMR data collected in many developing countries, including Brazil. In the latest survey, a few Gram-negative bacterial species resistant to carbapenems and cephalosporins have gained the status of 'critical priority' pathogens. In Brazil, cases of nosocomial infections caused by these bacteria have also increased significantly in recent years and new measures to combat these pathogens are needed. Given that carbapenems and cephalosporins are the most largely used antibiotics in the clinic today, the main objective of this study is to identify molecules that can recover the sensitivity to carbapenems and cephalosporins. Such molecules could therefore be used as adjuvants against carbapenem-resistant bacteria in combined drug therapies. For this purpose, the bacterium Xanthomonas citri, which has natural resistance to various antibiotics, including carbapenems and cephalosporins, will be used as a model organism for multidrug-resistant Gram-negative bacteria in phenotypic assays and screenings of compounds and drug libraries. In addition, the proposal aims to explore new targets and mechanism of action of compounds in Gram-negative bacteria that could drive the rational design of novel drugs. To this end, besides the screening of compounds from libraries of natural products still unexplored for antimicrobials, high throughput screening (HTS) assays will be performed to identify inhibitors of type-2 methionine-tRNA synthase, an enzyme that is essential for protein synthesis in Gram-negative bacteria and is which is considered a promising antimicrobial target. (AU)

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