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Antimicrobial activity and multi-targeted mechanism of action of suberanilic acid against methicillin-resistant Staphylococcus aureus

ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) is a major causative agent for common infectious diseases in the world. With the emergence of antibiotic resistance in clinical therapy, there is an urgent need to develop novel antimicrobial drugs that will overcome these shortfalls. Secondary metabolites of endophytic fungi are important sources of antimicrobial drug mining as they serve as alternative synthetic antibiotics due to their safety and multi-target efficiency. Suberanilic acid, an amide alkaloid from the endophytic fungus Pestalotiopsis trachycarpicola DCL44, has been identified as an important antimicrobial agent, however, the antibiotic properties of suberanilic acid on multi-drug resistant bacterial such as MRSA has not been fully investigated. Therefore, to investigate the potential antimicrobial mechanism of suberanilic acid against MRSA, a quantitative proteomics approach using tandem mass tagging (TMT) was used. The results demonstrated that suberanilic acid had multiple targets of action against MRSA, which included affecting ribosome synthesis, inhibition of membrane translocation of nutrient uptake (ABC transporter system), and energy metabolism of carbohydrates, and amino acid metabolism dysregulation. In conclusion, this study demonstrates that suberanilic acid has the potential to be used as an antimicrobial agent for the control of MRSA infections and provides a reference for the development of antimicrobial agents of endophytic fungal origin.

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Yanchun Hu

PROVIDER: PXD048581 | iProX | Sat Jan 13 00:00:00 GMT 2024

REPOSITORIES: iProX

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Project description:The rapid emergence of drug resistant Staphylococcus aureus (S. aureus), in particular, methicillin-resistant S. aureus (MRSA) poses a serious threat to public health globally. Reuse of metal-based antimicrobials stands for one of the most promising strategies to resensitize drug resistant bacteria to conventional antibiotics. Silver (Ag) has been used as an antimicrobial agent since antiquity, yet its molecular mechanism of action is elusive largely owing to technical challenges to identify the direct silver-binding protein targets accountable for its action. Herein, using an in-house developed hyphenated technique LC-GE-ICP-MS, we successfully separated and identified 38 authentic Ag+-binding proteins (Ag+-proteome) in S. aureus at the whole-cell scale for the first time. By integration with bioinformatic analysis and systematic biochemical characterizations, we captured the first snapshot on the dynamic action of Ag+ against S. aureus at the molecular level, i.e., Ag+ primarily targets glycolysis via inhibiting multiple enzymes and induces the elevation of ROS through functional disruption of redox homeostasis system at the late stage, leading to an upregulation of oxidative pentose phosphate pathway (oxPPP) to alleviate Ag+ stress. However, the activation of oxPPP is ultimately futile due to key oxPPP enzymes being inhibited by Ag+. We further validated that Ag+ could inhibit 6-phosphogluconate dehydrogenase, a key target from oxPPP through binding to His185 at the active site and morphing the shape of catalytic pocket by X-ray crystallography. Significantly, the multi-target mode of action of silver is accountable for its suppression of antibiotic selection effects towards S. aureus as well as its sustainable antimicrobial activity. Such a unique mode of action of Ag+ (and silver nanoparticles) led to enhanced efficacy of a broad range of antibiotics and resensitization of MRSA to antibiotics. Our study resolves the long-standing question of the molecular targets of silver in S. aureus and offers a novel insight into the sustainable bacterial susceptibility of silver, providing a potential approach for combating antimicrobial resistance.

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Antimicrobial activity and multi-targeted mechanism of action of suberanilic acid against methicillin-resistant Staphylococcus aureus

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