Staphylococcus aureus: Overview of Bacteriology, Clinical Diseases, Epidemiology, Antibiotic Resistance and Therapeutic Approach

Staphylococcus aureus is an important human pathogen that causes wide range of infectious conditions both in nosocomial and community settings. The Gram-positive pathogen is armed with battery of virulence factors that facilitate to establish infections in the hosts. The organism is well known for its ability to acquire resistance to various antibiotic classes. The emergence and spread of methicillin-resistant S. aureus (MRSA) strains which are often multi-drug resistant in hospitals and subsequently in community resulted in significant mortality and morbidity. The epidemiology of MRSA has been evolving since its initial outbreak which necessitates a comprehensive medical approach to tackle this pathogen. Vancomycin has been the drug of choice for years but its utility was challenged by the emergence of resistance. In the last 10 years or so, newer anti-MRSA antibiotics were approved for clinical use. However, being notorious for developing antibiotic resistance, there is a continuous need for exploring novel anti-MRSA agents from various sources including plants and evaluation of non-antibiotic approaches

Cheminformatic Approaches to Hit-Prioritization and Target Prediction of Potential Anti-MRSA Natural Products

>Magister Scientiae - MScThe growing resistance of Methicillin-Resistant Staphylococcus aureus (MRSA) to currently prescribed drugs has resulted in the failure of prevention and treatment of different infections caused by the superbug. Therefore, to keep pace with the resistance, there is a pressing need for novel antimicrobial agents, especially from non-conventional sources. Several natural products (NPs) have displayed varying in vitro activities against the pathogen but few of these natural compounds have been studied for their prospects to be potential antimicrobial drug candidates. This may be due to the high cost, tedious, and time-consuming process of conducting the important preclinical tests on these compounds. Hence, there is a need for cost-effective strategies for mining the available data on these natural compounds. This would help to get the knowledge that may guide rational prioritization of “likely to succeed” natural compounds to be developed into potential antimicrobial drug candidates. Cheminformatic approaches in drug discovery enable chemical data mining, in conjunction with unsupervised and supervised learning from available bioactivity data that may unlock the full potential of NPs in antimicrobial drug discovery. Therefore, taking advantage of the available NPs with their known in vitro activity against MRSA, this study conducted cheminformatic and data mining analysis towards hit profiling, hit-prioritization, hit-optimization, and target prediction of anti-MRSA NPs. Cheminformatic profiling was conducted on the 111 anti-MRSA NPs (AMNPs) retrieved from literature. About 20 current drugs for MRSA (CDs) were used as a reference to identify AMNPs with promising prospects to become drug candidates

Cheminformatic approaches to hit-prioritization and target prediction of potential anti-mrsa natural products

Magister Pharmaceuticae - MPharmThe growing resistance of Methicillin-Resistant Staphylococcus aureus (MRSA) to currently prescribed drugs has resulted in the failure of prevention and treatment of different infections caused by the superbug. Therefore, to keep pace with the resistance, there is a pressing need for novel antimicrobial agents, especially from non-conventional sources. Several natural products (NPs) have displayed varying in vitro activities against the pathogen but few of these natural compounds have been studied for their prospects to be potential antimicrobial drug candidates. This may be due to the high cost, tedious, and time-consuming process of conducting the important preclinical tests on these compounds. Hence, there is a need for cost-effective strategies for mining the available data on these natural compounds. This would help to get the knowledge that may guide rational prioritization of “likely to succeed” natural compounds to be developed into potential antimicrobial drug candidates

Cheminformatic approaches to hit-prioritization and target prediction of potential anti-mrsa natural products

Magister Pharmaceuticae - MPharmThe growing resistance of Methicillin-Resistant Staphylococcus aureus (MRSA) to currently prescribed drugs has resulted in the failure of prevention and treatment of different infections caused by the superbug. Therefore, to keep pace with the resistance, there is a pressing need for novel antimicrobial agents, especially from non-conventional sources. Several natural products (NPs) have displayed varying in vitro activities against the pathogen but few of these natural compounds have been studied for their prospects to be potential antimicrobial drug candidates. This may be due to the high cost, tedious, and time-consuming process of conducting the important preclinical tests on these compounds. Hence, there is a need for cost-effective strategies for mining the available data on these natural compounds. This would help to get the knowledge that may guide rational prioritization of “likely to succeed” natural compounds to be developed into potential antimicrobial drug candidates

Cheminformatic Characterization of Natural Antimicrob al Products for the Development of New Lead Compounds

The growing antimicrobial resistance (AMR) of pathogenic organisms to currently pre- scribed drugs has resulted in the failure to treat various infections caused by these superbugs. Therefore, to keep pace with the increasing drug resistance, there is a pressing need for novel antimicrobial agents, especially from non-conventional sources. Several natural products (NPs) have been shown to display promising in vitro activities against multidrug-resistant pathogens. Still, only a few of these compounds have been studied as prospective drug candidates. This may be due to the expensive and time-consuming process of conducting important studies on these compounds. The present review focuses on applying cheminformatics strategies to characterize, prioritize, and optimize NPs to develop new lead compounds against antimicrobial resistance pathogens. Moreover, case studies where these strategies have been used to identify potential drug candidates, including a few selected open-access tools commonly used for these studies, are briefly outlined

Metabolomics approaches to decipher the antibacterial mechanisms of yerba mate (\u3ci\u3eIlex paraguariensis\u3c/i\u3e) against \u3ci\u3eStaphylococcus aureus\u3c/i\u3e and \u3ci\u3eSalmonella enterica\u3c/i\u3e serovar Typhimurium

The increasing prevalence of drug-resistant pathogens is an urgent problem that requires novel methods of bacterial control. Plant extracts inhibit bacterial pathogens and could contain antibacterial compounds with novel mechanisms of action. Yerba mate, a common South American beverage made from Ilex paraguariensis, has antibiotic activity against a broad range of bacterial pathogens. In this work, an attempt was first made to characterize the antibacterial source of an aqueous yerba mate extract by generating a series of extract fractions, collecting GC-MS and antibacterial activity profiles, and then ranking the hundreds of compounds by their presence in fractions with high antibacterial activity. Quinic acid, quercetin, and 5-hydroxy pipecolic acid were highly ranked, suggesting an association between the antibacterial activity of yerba mate against methicillin-resistant Staphylococcus aureus (MRSA). Next, metabolites that accumulated in the supernatants of Salmonella Typhimurium and Lactobacillus casei cultures were surveyed for decreases in phenolic compounds that might signify metabolism of bioactive yerba mate components. No decreases in phenolic compounds were observed. The hypothesis that phenolic compounds might chelate iron as a mechanism of antibacterial activity was also tested; exogenous iron sulfate stimulated the partial recovery of S. Typhimurium to the inhibitory effect of yerba mate in a milk system. Finally, an assessment of potential antibacterial mechanisms of action was undertaken by surveying the metabolites produced by Salmonella Typhimurium in the presence of yerba mate extract and conducting assays to assess cell membrane integrity and catalase activity. No effect on the cell membrane was observed while catalase activity was reduced in the presence of yerba mate extract. Metabolomics revealed significant differences in central carbon metabolism, the cell wall precursor UDP-N-acetylglucosamine, the regulatory metabolites alpha-ketoglutarate and acetylphosphate, the energy metabolite NAD+, and a match to yohimbine, which has known antibacterial activity. Future work can move closer to understanding the antibacterial value of yerba mate extract and its constituents by testing specific mechanistic hypotheses based on metabolic alterations, further examining 5-hydroxy pipecolic acid and yohimbine for antibacterial activity and mechanism, and annotating currently unknown compounds that could have antibacterial activity or be additional key metabolites pointing to specific mechanisms of action

Investigating the antibacterial activity of novel metal complexes against antimicrobial resistant pathogens

Antimicrobial resistance (AMR) is one of the serious global health challenges of our time. There is an urgent need to develop novel therapeutic agents to overcome AMR, preferably through alternative mechanistic pathways from conventional treatments. Interdisciplinary research in inorganic medicinal chemistry with biology is advancing the knowledge and implementation of transition metal complexes for therapy and is offering a realistic alternative to traditional antibiotics. Metal complexes with 1,10-phenanthroline (phen) ligands have demonstrated promising therapeutic capabilities with diverse biological activity. Consequently, there has been a resurgence in research of these complexes as possible alternatives or adjuvants to established antimicrobial clinical therapeutics. The antibacterial and anti-biofilm activity of novel metal complexes (metal = Cu(II), Mn(II), and Ag(I)) incorporating phen and various dicarboxylate ligands was the focus of this research. The Cu(II), Mn(II), and Ag(I) chelates incorporating both phen and the dianion of 3,6,9-trioxaundecanedioic acid (tdda) were the most effective, and the activity varied depending on the metal centre. All three metal-tdda-phen complexes showed comparable and often superior activity to the established antibiotic gentamicin clinical P. aeruginosa isolates from cystic fibrosis (CF) lungs of Irish patients, concerning biofilm formation and established biofilms. Combination studies presented synergistic activity between all three complexes and gentamicin, particularly for the post-treatment of established mature biofilms, and were supported by the reduction of the individual biofilm components examined. The efficacy of individual treatments of Cu-tdda-phen, Mn-tdda-phen, and Ag-tdda-phen and in combination with gentamicin were further examined in vivo, utilising the larvae of Galleria mellonella infected with CF isolates. All test complexes were tolerated by G. mellonella in concentrations up to 10 µg/larva and affected the host\u27s immune response by stimulating immune cells (hemocytes) and enhancing the expression of genes that encode for immune-related peptides. Combining the metal-tdda-phen complexes with gentamicin further intensified this response at lower concentrations, clearing a P. aeruginosa infection previously resistant to gentamicin alone. Therefore, this work highlights the anti-pseudomonal capabilities of metal-tdda-phen complexes alone and combined with gentamicin in a valuable pre-clinical in vivo model

antibacTR : dynamic antibacterial-drug-target ranking integrating comparative genomics, structural analysis and experimental annotation

Background : development of novel antibacterial drugs is both an urgent healthcare necessity and a partially neglected field. The last decades have seen a substantial decrease in the discovery of novel antibiotics, which combined with the recent thrive of multi-drug-resistant pathogens have generated a scenario of general concern. The procedures involved in the discovery and development of novel antibiotics are economically challenging, time consuming and lack any warranty of success. Furthermore, the return-on-investment for an antibacterial drug is usually marginal when compared to other therapeutics, which in part explains the decrease of private investment. - Results : in this work we present antibacTR, a computational pipeline designed to aid researchers in the selection of potential drug targets, one of the initial steps in antibacterial-drug discovery. The approach was designed and implemented as part of two publicly funded initiatives aimed at discovering novel antibacterial targets, mechanisms and drugs for a priority list of Gram-negative pathogens: Acinetobacter baumannii, Escherichia coli, Helicobacter pylori, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. However, at present this list has been extended to cover a total of 74 fully sequenced Gram-negative pathogens. antibacTR is based on sequence comparisons and queries to multiple databases (e.g. gene essentiality, virulence factors) to rank proteins according to their potential as antibacterial targets. The dynamic ranking of potential drug targets can easily be executed, customized and accessed by the user through a web interface which also integrates computational analyses performed in-house and visualizable on-site. These include three-dimensional modeling of protein structures and prediction of active sites among other functionally relevant ligand-binding sites. - Conclusions : given its versatility and ease-of-use at integrating both experimental annotation and computational analyses, antibacTR may effectively assist microbiologists, medicinal-chemists and other researchers working in the field of antibacterial drug-discovery. The public web-interface for antibacTR is available at 'http://bioinf.uab.cat/antibactr'