Thiouracil SecA inhibitors: bypassing the effects of efflux pumps and attenuating virulence factor secretion in MRSA and Bacillus anthracis

Abstract

We have previously reported a series of thiouracil analogs as bacterial SecA inhibitors. In this study, one potent thiouracil analog, SCA-15, was further evaluated for its inhibitory effects on SecA proteins and against strains of methicillin-resistant Staphylococcus aureus (MRSA) and Bacillus anthracis Sterne. SCA-15 inhibited the ion-channel activities of SecA1 with IC 50 of 2.0-2.8 μM and the ATPase activities of SecA2 with IC 50 of 13-20 μM, respectively. Drug affinity responsive target stability (DARTS) and protein pull-down experiments further supported SaSecA1 and SaSecA2 as the targets of the inhibitor. SCA-15 showed promising bactericidal effects against MRSA and B. anthracis Sterne. In addition, SCA-15 could at least partially overcome the effects of efflux pumps responsible for multidrug resistance. Moreover, SCA-15 also inhibited the secretion of several important toxins of both S. aureus and B. anthracis. These results indicated that targeting SecA is a promising antimicrobial strategy against MRSA and B. anthracis.

Emerging Extracellular Molecular Targets for Innovative Pharmacological Approaches to Resistant Mtb Infection

“…Additionally, it was recently shown that the SecA2 pathway activates the ATK kinase checkpoint protein, resulting in the formation of double-strand breaks (DBSs) in host DNA [ 64 ]. Several compounds have been identified as potential inhibitors of Sec pathways, including analogs of the dye rose Bengal, thiouracil analogs and thiazolidine derivatives [ 65 , 66 , 67 ].…”

“…Efflux pumps play a crucial role in multi-drug resistance (MDR), often leading to suboptimal drug uptake. Interestingly, these compounds could also be interesting in overcoming the effect of efflux pumps that are responsible for MDR [66]. 5) were tested for anti-mycobacterial activity.…”