Alanine racemase (Alr), a PLP-dependent enzyme, plays an essential role in cell wall synthesis as it racemizes L-alanine to D-alanine, a key building block for peptidoglycan biosynthesis. Therefore, Alr has been established as an attractive antimicrobial drug target. Prior research on Alr sought to inhibit the enzyme by developing structural analogs of D-alanine. Unfortunately, these inhibitors suffer from lack of specificity as they act on other PLP-containing enzymes, including those found in humans. Therefore, Alr inhibitors that are not substrate analogs and can act through different mechanisms of enzyme inhibition are necessary for the therapeutic development of this drug target.<br/><i>M. tuberculosis</i> alanine racemase (MT-Alr), an anti-tuberculosis drug target, is an obligate homodimer. Both monomers contribute to the overall composition of their active sites. Therefore, disruption of the dimer interface could be used to inhibit MT-Alr activity. Seven potential MT-Alr hotspot residues (Glu72, Asp135, Asn139, Lys261, Glu267, Arg371 and Arg373) were identified using computational alanine scanning Robetta. The key hotspot residues responsible for MT-Alr dimerization were identified by systematic mutagenesis studies. This experimental verification could lead to the identification of potential ligand-binding sites at the MT-Alr dimer interface for inhibitor design.

Discovering novel antibiotics by employing a new approach to an old target

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.