The emergence of multidrug-resistant strains of pathogens demands strategies for developing novel antibacterial agents with known mechanisms of action. This paper presents a mechanistic investigation on the antibacterial effect of brominated BODIPYs, particularly, the 2,6-dibromo-1,3,5,7-tetramethyl-8-(4-acetamido)-4-bora-3a,4a-diaza-s-indacene, 3c against Staphylococcus aureus (MTCC 3160). Fluorescence microscopic images reveal that the compound 3c is internalized effectively within the bacterial cells, making it an ideal antibacterial compound. Antibacterial activity was evaluated by Agar well diffusion assay, MIC, MBC and SEM imaging. Further, to explore the target of action, molecular docking studies were performed with 22 selected proteins from S. aureus and DNA gyrase B was found to be the main target for the present BODIPY. The inhibitory concentrations of 3c was determined in gyrase supercoiling assays and confirmed that DNA gyrase activity was reduced significantly in the presence of the investigated BODIPY. The study provides insights about the mechanism of the action of 3c against S.aureus and can be considered as a promising lead structure for antibacterial coatings used in various biomedical applications.

 

           Multidrug-resistant Staphylococcus aureus (MRSA) has been reported as one of the main cause of nosocomial infections in the world and considered as one of the most difficult bacteria to treat in hospitalized patients. This bacterium is notorious for its ability to become resistant to multiple classes of antibiotics 1, 2. These infections are mainly originated from contaminated surgical instruments, respirators and catheters 3.  Control and prevention measures must be strictly applied to avoid these infections from occurring and so, there is an urgent need for new antibacterial agents against this bacterium which can be used especially in manufacturing of surgical equipments and catheters.

Defining targets and modes of action of these new antimicrobial compounds remains a major challenge in their discovery processes. In recent years, there were many reports for identification of new inhibitors for the currently available targets, such as peptidoglycan biosynthetic enzymes, ribosome, DNA gyrase, or folic acid biosynthesis, among which gyrase has an important position. Bacterial gyrase is a type II topoisomerase which catalyzes the introduction of negative supercoils into DNA, which is essential for DNA replication, elongation and transcription. It is essential in all bacteria, but absent in animals4. This makes them attractive targets for developing more effective antimicrobials to fight against common bacterial contaminants, particularly methicillin-resistant Staphylococcus aureus (MRSA). This prokaryotic type II topoisomerase consist of the subunits GyrA and GyrB, with different functional domains. The GyrA subunit is principally involved in DNA breakage and recombination of supercoiling reaction, whereas GyrB subunit is responsible for ATP hydrolysis reaction. The derivatives of dibromopyrrolamides, coumarin, thiophene, pyrazole, quinolone, etc., are potent inhibitors against DNA gyrase B and are well established.5–8 However, the increased prevalence of multidrug resistance shown by S. aureus explains the current relevance of new classes of DNA gyrase inhibitors.9

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           BODIPYs have become one of the cornerstones in biotechnology due to their prospective application in biomolecular labeling, medical diagnosis, drug delivery, cellular pH, viscosity sensing,etc.10–13 Their biological properties particularly, antimicrobial, anticancer, etc. are well reported in literature.13–17 BODIPYs featuring iodine atoms on 2,6-positions are used in in vitro photodynamic antimicrobial chemotherapy were proved to be effective against S. xylosus, E. coli and P. aeruginosa.15,16 The halogenated dyes with their heavy atom effect display efficient intersystem crossing and act as photosensitizers via formation of reactive singlet oxygen species to exhibit photocytotoxicity.18 Apart from this key cytotoxic mechanism, no other well established antibacterial mechanism has been reported for halogenated BODIPYs. Hence, it is been very interesting to report here DNA gyrase inhibition of brominated BODIPYs which also contribute towards their marked antibacterial property. In the present work, the antibacterial activity of 2,6-dibromo BODIPYs against S. aureus was evaluated.  As the electronic structure of a molecule has key role in inducing toxicity, BODIPYs containing thiophene ring and an amide group were selected.19 The antimicrobial activity of cationic BODIPY derivatives is well described;13,15,20in literature,  however there is no reports for antibacterial activity of  uncharged ones. Here, we explore the mechanism of action of uncharged BODIPYs via in silico analysis and has been validated by in vitro studies. To the best of our knowledge, this paper reports for the very first time, 2,6-dibromo BODIPY as a novel inhibitor of DNA gyrase of S. aureus and we anticipate that the compound 3c is a promising lead structure for various medical applications.

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