SecA Inhibitors Block Growth of Methicillin-Resistant Staphylococcus aureus

A novel class of low molecular weight compounds has been shown to effectively inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA), one of the most serious drug-resistant bacterial pathogens.

Investigators at Georgia State University (Atlanta, USA) had shown previously that small molecular components of the dye Rose Bengal (RB) were active against the bacteria Escherichia coli and Bacillus subtilis. This activity was found to be due to inhibition of SecA, a cell membrane-associated subunit of the eubacterial Sec or Type II secretory pathway, a system which is responsible for the secretion of proteins through the cell membrane. Within this system SecA has the functional properties of an ATPase and is required to empower the movement of the protein substrate across the translocation channel. Thus, SecA is a key component of the general bacterial secretion system required for viability and virulence.

In the current study, which was published in the November 1, 2015, issue of the journal Bioorganic & Medicinal Chemistry, the investigators evaluated two potent RB analogs for activities against MRSA strains and for their mechanism of actions.

These analogs inhibited the ATPase activities of S. aureus SecA1 (SaSecA1) and SecA2 (SaSecA2), and inhibited the SaSecA1-dependent protein-conducting channel. Moreover, these inhibitors reduced the secretion of three toxins from S. aureus and exerted potent bacteriostatic effects against three MRSA strains.

The best inhibitor, SCA-50, showed potent concentration-dependent bactericidal activity against MRSA Mu50 strain and very importantly, two to 60-fold more potent inhibitory effect on MRSA Mu50 than all the commonly used antibiotics including vancomycin, which is considered the last resort option in treating MRSA-related infections.

Deletion or overexpression of bacterial efflux pumps had minimal effect on the antimicrobial activities against S. aureus, indicating that the effects of SecA inhibitors were not affected by the presence of these efflux pumps. This study showed that these small molecule analogs of Rose Bengal targeted SecA functions, had potent antimicrobial activities, reduced the secretion of toxins, and had the ability to overcome the effect efflux pumps, which are responsible for multi-drug resistance.

"We have found that SecA inhibitors are broad-spectrum antimicrobials and are very effective against strains of bacteria that are resistant to existing antibiotics," said contributing author Dr. Binghe Wang, professor of chemistry at Georgia State University.

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