In This Issue pubs.acs.org/journal/aidcbc
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DEVELOPING PHOTOSWITCHABLE ENZYME INHIBITORS FOR ANTIMICROBIAL CHEMOTHERAPY
Mtb cell envelope. These molecules may pave the way toward novel tuberculosis therapeutics.
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The increasing rise in antimicrobial resistance poses a problem to the successful treatment of bacterial infections. This necessitates the development of alternate treatment options to combat this significant threat. In this issue, Fuchter and co-workers (DOI: 10.1021/ acsinfecdis.6b00148) report the development of photoswitchable inhibitors for bacterial amidohydrolase enzymes, which are homologues of human histone deacetylases (HDACs). These enzymes are often found in microorganisms resistant to various hospital-acquired infections and deaths. The authors built on their previous work on amidohydrolase ligands to develop photoswitchable inhibitors containing azobenzene and azopyrazole moieties. They successfully demonstrate inhibitory activity of the target enzymes and provide the first protein− ligand crystal structures of these ligands bound to bacterial amidohydrolase. This study highlights potential alternate mechanisms to combat antibiotic resistant microorganisms.
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Human cytomegalovirus (HCMV) generally does not affect healthy individuals, but it can lead to serious health problems in newborns and immunocompromised individuals. Limited efficacy, toxicity, and emerging drug resistance restrict the current armamentarium of anti-HCMV agents, thus necessitating the development of novel therapeutics. In this issue, Coen et al. (DOI: 10.1021/acsinfecdis.6b00079) studied the interaction of the human cytomegalovirus DNA polymerase catalytic subunit UL54 and an accessory subunit, UL44, as a potential target for new antiviral drugs. The authors identified a small covalent and selective inhibitor of this protein−protein interaction via a highthroughput screen that was shown to block long-chain DNA synthesis. A cocrystal structure of the compound bound to the UL44 subunit revealed its allosteric binding mode and the relevant residues involved in the inhibitory action. The findings of this study could lead to the development of novel medicines for the treatment of human cytomegalovirus infections.
MYCOBACTERIUM TUBERCULOSIS INHIBITORS THAT TARGET THE PROTEASOME
Mycobacterium tuberculosis (Mtb) is a global threat due to its lethality and increasing drug resistance. Therefore, the development of safe and effective therapeutics is crucial. One recently identified drug target of Mtb is the 20S peptidase of the proteasome, which is unusual as it is nonessential to survival of the microorganism. In this issue, Sello et al. (DOI: 10.1021/acsinfecdis.6b00172) report the design and synthesis of species-selective inhibitors of the Mtb 20S. The authors based their compounds on the enzyme’s unique substrate preferences and on binding modes of covalent inhibitors of eukaryotic proteasomes known as syringolins. The authors created several syringolin analogues that demonstrated significant selectivity for Mtb 20S over its human homologue. Additionally, the compounds were capable of penetrating the © 2017 American Chemical Society
IDENTIFICATION OF A HUMAN CYTOMEGALOVIRUS INHIBITOR
Received: January 24, 2017 Published: February 10, 2017 111
DOI: 10.1021/acsinfecdis.7b00016 ACS Infect. Dis. 2017, 3, 111−111
