Drug Development against Acinetobacter baumannii by Screening a Drug Library Using a Metabolic Assay for Repurposing Drugs for Treatment

Date
2022
Authors
Irfan, Andleeb
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Abstract

Acinetobacter is commonly found in soil and water. There are many species of this bacteria. The growing threat to humans is from Acinetobacter baumannii infections. A. baumannii is a Gram-negative, nosocomial bacterium that can cause death if left untreated. A. baumannii causes infections in the lungs, blood, open wounds on body surfaces, and urinary tract infections. It can live for longer periods in the respiratory tract without symptoms. A. baumannii got the symbolic name of "Iraqibacter" for infecting many soldiers. A. baumannii is a highly manipulative, opportunistic, and very successful pathogen. It belongs to the class of ESKAPE bacteria and evades antibiotics by exploiting new ways to escape antibiotics and survive inside the host body. The WHO declared A. baumannii to be the most serious ESKAPE pathogen. Currently, due to the emergence of multi-drug resistant (MDR) A. baumannii, there is a huge demand to search for new medicinal compounds that can more effectively treat A. baumannii infections. A. baumannii is spread largely in the ICU and in patients who are hospitalized for longer periods. Thus, it is crucial to find new drug alternatives for A. baumannii infections. Many new strategies including nanotechnology, phage therapy, bactericidal gene therapy, and combination drug therapies are in the preliminary stages of development for A. baumannii infections. The main goal of my research work was to screen a repurposing drug library to find lead compounds that effectively inhibit in vitro growth of A. baumannii clinical strains, such as those obtained from injured military personnel. I screened 1500 drugs from the Prestwick drug library using an XTT colorimetric assay to measure bacterial metabolic activity in a spectrophotometer. Four identified potential anti-Acinetobacter drugs (Nitroxoline, Alexidine dihydrochloride, Methacycline hydrochloride, and Meclocycline sulfosalicylic plus Erythromycin as a control) were further characterized to define their Minimum Inhibitory Concentrations (MIC) against a large number of clinical A. baumannii isolates. I found various drug susceptibility profiles among the tested bacterial strains suggesting diverse drug resistant mechanisms were acquired in these isolates. Therefore, further in-depth studies are needed to formulate a drug cocktail that can be applied to treat a broad range of clinical A. baumannii infections.

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Keywords
A.Baumannii, Acinetobacter baumannii, Drug Development, Drug Library Screening, ESKAPE, Prestwick Library, XTT
Citation
Department
Molecular Microbiology and Immunology