SecA, a key component of bacterial Sec-dependent secretion pathway, is an attractive target for exploring novel antimicrobials. Rose bengal (RB), a polyhalogenated fluorescein derivative, was found from our previous study as a potent SecA inhibitor. Here we describe the synthesis and structure-activity relationships (SAR) of 23 RB analogues that were designed by systematical dissection of RB. Evaluation of these analogues allowed us to establish an initial SAR in SecA inhibition. The antimicrobial effects of these SecA inhibitors are confirmed in experiments using E. coli and B. subtilis.
SecA, a key component of bacterial Sec-dependent secretion pathway, is an attractive target for novel antimicrobial development. Through a combination of virtual screening and experimental exploration of surrounding chemical space, we identified a hit bistriazole SecA inhibitor, SCA-21, and studied a series of analogs by systematic dissections of the core scaffold. Evaluation of these analogs allowed us to establish an initial SAR in SecA inhibition. The best compounds in this group have potent inhibition activity of SecA-dependent protein-conducting channel activity and protein translocation activity at low to sub-μM concentrations. They also have MIC values against various strains of bacteria that are correlated with the SecA and protein translocation inhibition data. These compounds are effective against methicillin-resistant Staplylococcus aureus strains with various levels of efflux pumps, indicating the ability to null the effect of multiple-drug resistance with SecA inhibitors. Results from studies of drug affinity responsive target stability and protein pull-down assays are consistent with SecA as a target for these compounds.
There is a consensus in the medical profession of the pressing need for novel antimicrobial agents due to issues related to drug resistance. In practice, solutions to this problem to a large degree lie with the identification of new and vital targets in bacteria and subsequently designing their inhibitors. We consider SecA a very promising antimicrobial target. In this review, we compile and analyze information available on SecA to show that inhibition of SecA has a multitude of consequences. Furthermore, we discuss issues critical to the design and evaluation of SecA inhibitors.
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