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Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies

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Monika I. Konaklieva, Ph.D.
Department of Chemistry
American University
Washington, DC USA

 

Monika I. Konaklieva is a professor of chemistry at American University, Washington, DC, and her training and experience are in the areas of synthetic organic chemistry and structural drug design. The discovery of scaffolds best fitted for antibacterial drug development is challenging. Differences in the requirements for drug development for gram-negative versus gram-positive increases the challenges innate to any drug discovery effort, especially for broad-spectrum antibacterials. There are two distinct advantages of starting from a natural product scaffold during lead optimization via different synthetic approaches: the coevolution of a high affinity for a biological target and the ability to reach the cellular site of action. We have designed a novel class of non-transpeptidase, b-lactamase resistant monocyclic b-lactams. They exhibit inhibitory and cidal activity against serine b-lactamase producing Mycobacterium tuberculosis wild type strain and multiple b-lactamase producing Moraxella catarrhalis clinical isolates. The antimicrobial activity of monocyclic β-lactams lacking the ionizable group at N1 have demonstrated that new antibiotic leads could be identified for the treatment of specific drug-resistant, β-lactamase producing bacterial pathogens without the need for β-lactamase inhibition.

Although reports emerged as early as 1940 that some strains of bacteria can exhibit resistance to penicillin, this had no clinical relevance until the 1970s. Today, resistance to antibiotics is a global crisis with multiple drug resistance (MDR) and extreme drug resistance (XDR) reported in both community and healthcare settings. Now, in the early 21st century, the search for new antibacterial agents and novel strategies for combating bacterial resistance remains urgent and extremely challenging. Our developing understanding of the nontraditional roles of the β-lactams as inhibitors of different bacterial enzymes, illustrative to design-to-function strategy, is leading us to their use as platforms for the design of new therapeutic agents.

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Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies


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March 20, 2019