In Silico Structure-Based Screening of Large Ligand Library Against Virulence Factors of Drug Resistant Pathogens
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2019, Vol 18, Issue 5
Abstract
The emergence of drug-resistant microbes is an alarming threat to the global population. There is an urgent need of effective drugs against these pathogens. Among these, SA and MTB are especially problematic to human. The global spread of MRSA is of great concern in the treatment of Staphylococcal infections because it is quickly acquiring resistance to all clinical antibacterial agents. A novel approach of drug development is to target virulence factors, which can potentially prevent drug-resistance from building up. An early secretory SA protein EsxA is known to be a virulence factor which plays a major role in the pathogenesis of the bacterium. Therefore, EsxA is a promising drug target. An in-silico platform has been setup to perform structure-based screening of a large compound library containing 6.8 million lead-like and bioactive ligands against EsxA. Clustering analysis on the docking results led to the prediction of 5 important binding sites on EsxA. Out of the top 100 docking score compounds, 5 hit compounds were validated by secondary screening using NMR titration experiment. One hit compound (6058448) showed a MIC of 25uM by broth microdilution assay and one hit compound (5674203) showed anti virulence effects by inhibiting the expression of protein A and alpha-toxin virulence factors of SA. The present study using the in-silico structure-based screening platform has laid the foundation for drug development targeting EsxA. The resulting confirmed hit compounds will be useful leads to develop therapeutic drugs to combat MRSA.The discovery and continual development of antibiotics since the 1940s have greatly reduced the mortality rate of infectious diseases. However, newly emerging and reemerging of drug-resistant microbes mean that despite our best efforts, infectious diseases remain a great threat to humanity today [1]. Among these, Staphylococcus Aureus and Mycobacterium tuberculosis (MTB) are especially problematic. S. aureus is a highly adaptive gram-positive bacterium and commensal of the human skin and nostrils [2]. S. aureus is a common cause of minor skin and wound infections, but can also cause serious and even fatal infections, particularly in the immunocompromised persons. Methicillin-resistant Staphylococcus Aureus (MRSA) infection is becoming an alarming local and global threat, in particular the number of both hospital-acquired and community-acquired cases are rising, leading to many life-threatening diseases such as endocarditis, pneumonia and toxic shock syndrome [3]. MRSA has been endemic in Hong Kong since the mid-1980s. Approximately 70% and 58% of the total and blood culture isolates of S. aureus in Hong Kong public hospitals are MRSA, respectively [4]. MRSA is getting more resistant to antibiotics that are currently used, and even a glycopeptides resistant strain, Vancomycin-resistant S. aureus (VRSA) has also been reported [5]. Similarly, MTB, the causative agent of tuberculosis, is still a major potential threat. Globally, an estimation of 9.6 million people had suffered from TB, and among these, about 16%, or 1.5 million, were killed [6]. It was estimated that 3.3% of new TB cases are multidrug-resistant tuberculosis (MDR-TB), and 20% of previously treated cases are MDR-TB, which are significant numbers [6]. MDR-TB is extremely difficult to cure, with a treatment success rate of merely 50% [6]. Furthermore, an even more resistant form of TB, totally drug-resistant TB (TDR-TB) has been described [7]. With resistance to all tested drugs, TDR-TB might be untreatable by any currently available drugs [8]. Therefore, there is a definite need to develop new approaches and druggable targets for combating drug-resistant pathogens.
Authors and Affiliations
Timothy Tin Mong Yung, Pok Man Lai, Ting Zhou, Man Kit Tse, Richard Yi Tsun Kao, Kwok Yung Yuen, Kong Hung Sze
Keywords
Related Articles
- EP ID EP622739
- DOI 10.26717/BJSTR.2019.18.003202
- Views 166
- Downloads 0
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