title: Design, Synthesis and Evaluation of Triazole-Pyrimidine Analogues as SecA Inhibitors.
abstract: SecA, a key component of the bacterial Sec-dependent secretion pathway, is an attractive target for the development of new antimicrobial agents. Through a combination of virtual screening and experimental exploration of the surrounding chemical space, we identified a hit bistriazole SecA inhibitor, SCA-21, and studied a series of analogues by systematic dissections of the core scaffold. Evaluation of these analogues allowed us to establish an initial structure-activity relationship in SecA inhibition. The best compounds in this group are potent inhibitors of SecA-dependent protein-conducting channel activity and protein translocation activity at low- to sub-micromolar concentrations. They also have minimal inhibitory concentration (MIC) values against various strains of bacteria that correlate well with the SecA and protein translocation inhibition data. These compounds are effective against methicillin-resistant Staphylococcus aureus strains with various levels of efflux pump activity, indicating the capacity of SecA inhibitors to null the effect of multidrug resistance. Results from studies of drug-affinity-responsive target stability and protein pull-down assays are consistent with SecA as a target for these compounds.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Jianmei
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Biology, Center for Biotechnology and Drug Design, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Jinshan
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Arpana Sagwal
authors.initials: AS
authors.lastname: Chaudhary
authors.affiliation: Department of Biology, Center for Biotechnology and Drug Design, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Ying-hsin
authors.initials: YH
authors.lastname: Hsieh
authors.affiliation: Department of Biology, Center for Biotechnology and Drug Design, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Dai
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Krishna
authors.initials: K
authors.lastname: Damera
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Weixuan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Biology, Center for Biotechnology and Drug Design, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA. biopct@gsu.edu.
authors.forename: Phang C
authors.initials: PC
authors.lastname: Tai
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA. wang@gsu.edu.
authors.forename: Binghe
authors.initials: B
authors.lastname: Wang
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D000069816:SEC Translocation Channels; D000081416:SecA Proteins; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D011743:Pyrimidines; D000069816:SEC Translocation Channels; D014230:Triazoles; D000251:Adenosine Triphosphatases; D000081416:SecA Proteins; C030986:pyrimidine
keywords: SecA inhibitors; antimicrobials; protein secretion; pyrimidines; triazoles