In Silico Method for the Screening of Phytochemicals against Methicillin‐Resistant Staphylococcus Aureus

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) has evolved resistance even against the last resort β-lactam antibiotics. This is because of the acquisition of an additional penicillin-binding protein 2a (PBP2a) which is a resistance determinant in MRSA. Currently, available PBP2a inhibitors are ineffective against life-threatening and fatal infections caused by microorganisms. Therefore, there is an urgent need to screen natural compounds that could overpass the resistance issue alone or in combination with antibacterial drugs. We studied the interactions of different phytochemicals with PBP2a so that crosslinking of peptidoglycans could be inhibited. In structure-based drug designing, in silico approach plays a key role in determining phytochemical interactions with PBP2a. In this study, a total of 284 antimicrobial phytochemicals were screened using the molecular docking approach. The binding affinity of methicillin, -11.241 kcal/mol, was used as the threshold value. The phytochemicals having binding affinities with PBP2a stronger than methicillin were identified, and the drug-likeness properties and toxicities of the screened phytochemicals were calculated. Out of the multiple phytochemicals screened, nine were found as good inhibitors to be PBP2a, among which cyanidin, tetrandrine, cyclomorusin, lipomycin, and morusin showed strong binding potential with the receptor protein. These best-selected phytochemicals were also docked to the allosteric site of PBP2a, and most of the compounds revealed strong interactions with the allosteric site. These compounds were safe to be used as drugs because they did not show any toxicity and had good bioactivity scores. Cyanidin had the highest binding affinity (S-score of -16.061 kcal/mol) with PBP2a and with high gastrointestinal (GI) absorption. Our findings suggest that cyanidin can be used as a drug against MRSA infection either in purified form or that its structure can lead to the development of more potent anti-MRSA medicines. However, experimental studies are required to evaluate the inhibitory potential of these phytochemicals against MRSA.

In silico studies of benzimidazole derivatives as sustainable inhibitors against Methicillin-resistant Staphylococcus aureus

“…2 kcal/mol. Also, the proposed compounds showed favourable in silico ADMET properties, although several antibiotics have been known to cause side effects such as diarrhoea, vomiting, and weight loss [8]. The benzimidazole derivatives explored in the docking studies are potential transpeptidase domain antagonists to be considered for further optimization and development into effective inhibitors.…”

“…The transpeptidase domain containing the Ser403 amino acid responsible for resistance in MRSA was selected as the main active site. The protein had an allosteric site which serves as a regulatory system that affects the activity at the main binding site [8,9,25].…”

“…Some of the common bacteria that cause some chronic diseases include Mycobacterium tuberculosis associated with tuberculosis [5], Escherichia coli associated with intestinal infections, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumonia [6,7]. S. aureus is one of the most common gram (+) bacteria, it is responsible for a wide range of clinical infections including skin and soft tissue infections that can develop into bone infections or severe muscle pain [8]. It can also affect the lungs and heart valves if not treated.…”

“…It can also affect the lungs and heart valves if not treated. They are significant contributors to food-borne illness [8].…”

“…Studies show that the bacterial cell wall of S. aureus contains peptidoglycans which are the main building blocks and thus influence its survival during cell division and growth [8,9]. In S. aureus, resistance is initiated by the Penicillin-binding protein (PBP2A), a peptidoglycan transpeptidase in conjunction with the PBP2 transglycosylase domain when β-lactam antibiotics are introduced [9].…”