Identification of 1-chloro-2-formyl indenes and tetralenes as novel antistaphylococcal agents exhibiting sortase A inhibition

• Published in: Applied microbiology and biotechnology Vol. 98; no. 5; pp. 2041 - 2051
• Main Authors: Kahlon, Amandeep Kaur, Negi, Arvind S, Kumari, Ruma, Srivastava, Kishore K, Kumar, Shiv, Darokar, Mahendra P, Sharma, Ashok
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.03.2014; Springer Berlin Heidelberg; Springer; Springer Nature B.V
• Subjects: absorption; Aminoacyltransferases - antagonists & inhibitors; Aminoacyltransferases - genetics; Analysis; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - toxicity; Antibacterial agents; Antibiotics; Antimicrobial agents; Bacteria; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; bioassays; Biomedical and Life Sciences; Biotechnologically Relevant Enzymes and Proteins; Biotechnology; Cell Line; Cell Survival - drug effects; cell viability; Computational Biology; Cysteine Endopeptidases - genetics; Cytotoxicity; DNA, Bacterial - chemistry; DNA, Bacterial - genetics; Drug resistance; Drug therapy; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; Enzymes; excretion; extracellular matrix; fibronectins; Gram-positive bacteria; Humans; Indenes - pharmacology; Indenes - toxicity; Life Sciences; Liver cancer; mechanism of action; Metabolism; Microbial Genetics and Genomics; Microbial Sensitivity Tests; Microbiology; Molecular Docking Simulation; Molecular Sequence Data; Mycobacterium tuberculosis; Pathogens; Peptides; Proteins; Sequence Analysis, DNA; sortase A; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Staphylococcus aureus infections; Staphylococcus infections; Studies; Virulence; India; Anti-infectives; Sortase A; Antibacterials; Indenes; Tetralenes
• ISSN: 0175-7598; 1432-0614
• DOI: 10.1007/s00253-013-5036-1

Tetralene and indene compounds have shown inhibitory activity against human pathogen, Mycobacterium tuberculosis. Their potential use as antistaphylococcal agent against drug-resistant Staphylococcus aureus has not been explored so far. We determined in vitro antistaphylococcal activity and mechanism of action of these compounds as sortase A inhibitors through in silico analysis followed by biological assays. Tetralene and indene series were tested against S. aureus strains MTCC96, MRSA, and VA30. Three compounds showed significant reduction in MIC in both wild-type and drug-resistant S. aureus strains. In silico absorption, distribution, metabolism, excretion, and toxicity analysis of identified leads and cytotoxicity testing with colorimetric method using Vero and WRL-68 cell lines showed no significant cytotoxic effects. Molecular docking of these molecules with sortase A (PDB: 2KID) showed H-bond interaction with functional site residue Arg197 of sortase A. Sortase A inhibition assay was developed by expressing SrtA∆N from S. aureus strain MTCC96. Tetralene and indene compounds were found to have sortase A inhibitory potential. S. aureus strain MTCC96 treated with these compounds showed surface-sorting inhibition of fibronectin-binding protein and reduction in adherence to host extracellular matrix protein, fibronectin. 1-Chloro, 2-formyl, 6-methoxy, 1-tetralene (Tet-5), 1,5-dichloro, 2-formyl, 1-indene (Tet-20) and 1-chloro, 2-formyl, 5,6-methylenedioxy, and 1-indene (Tet-21) exhibited antistaphylococcal activity along with sortase A inhibition. The results also indicate the possible role of these leads in other reactions essential for cell viability.