Discovery of Novel Inhibitors of Multidrug-resistant Acinetobacter baumannii

Publication date: Available online 9 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Iswarduth Soojhawon, Nagarajan Pattabiraman, Arthur Tsang, Amanda L. Roth, Ellen Kang, Schroeder M. Noble
The recent emergence of multidrug-resistant Acinetobacter baumannii strains and the non-efficacy of currently available antibiotics against such infections have led to an urgent need for the development of novel antibacterials. In an effort to address this problem, we have identified three novel inhibitors, namely, D5, D12 and D6 using in silico screening with a homology model of the outer membrane protein W2 (OmpW2) from A. baumannii, as the proposed new drug target. OmpW is an eight-stranded β-barrel protein involved in the transport of hydrophobic molecules across the outer membrane and maintenance of homeostasis under cellular stress. The antimicrobial activities of compounds D5, D12 and D6 were evaluated against a panel of clinical isolates of A. baumannii strains. These compounds inhibited the growth of the strains with minimum inhibition concentration (MIC) ranges of 1 to 32 μg/ml. Time-kill kinetic studies with the highly virulent and drug resistant strain, A. baumannii 5075, indicated that D6 exhibited the highest bactericidal activity as a ≥ 3 log10 CFU/mL (99.9%) reduction in colony count from the initial inoculum was observed after 30 minutes incubation. D5 and D12 reduced at least 1log10 CFU/mL (90%) of the initial inoculum after 24 hours. In conclusion, these three lead inhibitors have provided two distinct chemical scaffolds for further analog design and optimizations, using chemical synthesis, to develop more potent inhibitors of the pathogen.

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