In This Issue pubs.acs.org/acschemicalbiology
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DARTING THE ANTIBIOTIC RESISTANCE ISSUE
The growing number of bacterial strains resistant to current antibiotic therapies is a global health concern. Many of the historically successful small molecule antibiotics target enzymes involved in the synthesis of the bacterial cell wall. However, despite intense efforts, few new small molecule drugs are on the horizon, and the landscape is particularly sparse for compounds targeting drug resistant bacterial strains. Now, Fura et al. (DOI: 10.1021/cb5002685) present an immunological approach, called D-amino acid antibody recruitment therapy, or DART, toward combating pathogenic bacteria. Key to their strategy is the exploitation of the promiscuity of the enzymes that incorporate D-alanine in the bacterial cell wall, which are key antibiotic drug targets. The authors attach the antibody-recruiting compound 2,4-dinitrophenyl to various Damino acids, and identify one that gets incorporated into the bacterial cell wall. They show that this enables the recruitment of anti-DNP antibodies to the bacteria, laying the groundwork for the development of an antibody-based immune therapy for bacterial infections.
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Infection with the hepatitis C virus (HCV) is linked to chronic hepatitis and liver cancer. The virus gains entry into liver cells through interactions between viral envelope proteins and receptors on liver cell surface, but it is not clear which receptor facilitates the infection process. Notably, the viral envelope proteins are heavily glycosylated, suggesting that glycan−lectin interactions may play a role in modulating the entry process. Now, Chen et al. (DOI: 10.1021/cb500121c) use surface plasmon resonance to explore the binding affinity of different glycoforms of the HCV envelope proteins and various lectin and nonlectin liver cell receptors. The authors determine that the strength of the interactions with the various receptors depends on the glycan structure on the envelope proteins. While some glycoforms interact more strongly with certain lectins, others have higher affinity for nonlections. These differences likely facilitate modulation of the cell entry process. These insights will guide future efforts to design effective therapeutic agents for HCV infection.
TARGETING TUBERCULOSIS WITH THIENOPYRIMIDINES
Mycobacterium tuberculosis, the causative agent of tuberculosis, killed over one million people in 2012 and infected nearly nine million more, underscoring the urgent need for new strategies to combat this increasingly drug-resistant pathogen. AlbesaJové et al. (DOI: 10.1021/cb500149m) report the synthesis, biological activity, and biochemical characterization, including investigation of the mechanism of action, of novel thienopyrimidines capable of killing both replicating and non-replicating M. tuberculosis. Synthesis of a series of thienopyrimidines led to the discovery of TP053, which exhibited potent activity against M. tuberculosis growth. To probe the mechanism of its activity, the authors generated mutant M. tuberculosis strains and identified a gene, Rv2466c, that conferred resistance to TP053. Using a combination of genetic, biochemical, and crystallographic methods, they were able to determine that TP053 is a prodrug that is activated by Rv2466c. These insights will facilitate development of thieopyrimidine-based compounds as potential therapeutic agents for tuberculosis. © 2014 American Chemical Society
HOW HCV GAINS ENTRY
Published: July 18, 2014 1390
dx.doi.org/10.1021/cb500506v | ACS Chem. Biol. 2014, 9, 1390−1390
