Insilico Identification 0f Putative Drug Targets In Staphylococcus Aureus

The currently known targets of staphylococcus aureus include PBP (penicillin binding protein) of peptidoglycan biosynthesis pathway. Previously, beta-lactam antibiotics were knows to be effective against them, but due to production of altered form of PBP protein as well as beta-lactamase enzyme synthesis those drugs are not effective now, hence, our current study involves identifying targets apart from PBP(Hao et al., 2012). Another antibiotics prescribed is fluroquinolone. Fluroquinolone target DNA Gyrase A enzyme-essential for the replication, supercoiling of DNA. But according to Stephen et al., a highly signification associate between levofloxaxin and ciprofloxacin treatment and subsequent isolation of MRSA is reported (Weber et al., 2003). Linezolid, a new class of antibiotic called oxazolidinones is used to treat MRSA, which involve the mechanism of binding to bacterial 23s ribosomal RNA but  of the 50s subunit and thus inhibiting the formation of functional 70s initiation complex but between April 13 and June 26 ,2008,12 patient were identified by LRSA (linezolid resistant staphylococcus aureus). All the isolates were detected with a point mutation in 23s RNA. It was concluded that the clinical outbreak of LRSA medicated by the (Fr gene was related with extensive usage of linezolid (Tsiodras et al., 2001).   In this study, we have tried to search for some potential therapeutic targets other than the target discussed above. We have implemented an approach considering two pathogen in the senses that it must be associated with replication as well as viability of the pathogen. Secondly, the target should not be homologous to human. The non homologous property of these proteins helps to establish highly selective drug against the pathogen preventing the possibility of the cross reaction.

With the human host this may help to minimize the side effect of the proposed drug (skaharkar et al.,2001). By this approach, we have found some targets which are not only essential and non-homolog but also bypass the resistant mechanism of existing targets and some targets are involved in the metabolic pathway of pathogen of which is not exploited as potential target area (Nathan et al ., 2004). We have also identified the membrane-bound essential, non-human homolog proteins emphasizing the fact  that 60% of the drug target is membrane-bound (arinaminpathy et al., 2009). 

            Staphylococcus aureus is an important pathogen causing a wide range of infection in the hospital and community setting. In order have adequate information for treatment of staphylococcus aureus infections, it is crucial to understand the trend in the antibiotic-resistance patterns. In addition, the occurrence and changes in types of staphylococcus aureus, colonial identities, and their geographic spread is essential for the establishment of adequate infection control programmes. In this study, 68 staphylococcus aureus isolates obtained from clinical and non-clinical sources Nigeria  between January and April 2009 were characterized using phenotype and molecular method.

              Staphylococcus areus can exemplify better than any other human pathogen the adaptive evolution of bacteria in the antibiotic era, as it has demonstrated a unique ability to quickly respond to each new antibiotic with the development of a resistant mechanism, starting with penicillin and methicillin, until the most recent linezolid and daptomycin. Resistant mechanism included inactivation of the antibiotic (penicillinase and aminogylcoside-modification enzymes) alteration of the target with decrease affinity for the antibiotic notable example being penicillin-binding protein 29 of methicillin-resistant Staphylococcus aureus and D-ala-D-lac of peptidoglycan precursors of Vancomycin-resistant strains]and afflux pumps [fluroquinolone and tetracycline].Complex genetic arrays[Staphylococcus chromosomal cassette mechanism elements or the Van A Operonl have been acquired by Staphylococcus aureus through horizontal gene transfer, while  resistance to other antibiotics, including some of the most recent ones [e.g fluroquinolones linezolid and daptomycin have developed through spontaneous mutations and positive selection. Detection of the resistance mechanisms and their genetic basis is an important support antibiotics susceptibility and surveillance in Staphylococcus aureus.

    The need for new drugs comes from the widespread resistance to those in current use. New drugs targets are required to allow the discovery of chemically diverse effective drugs. The search for such new targets and new drug chemo types will likely be helped by the advent of functional genomics and structure-based drug design. After validation of the putative targets as those capable of providing effective and safe drugs, targets can be used as the basis for screening compounds in order to identify new leads, which in turn, will qualify for lead optimization work. Many enzyme in macromolecular and metabolite synthesis are promising potential targets, some of which have been established in many micro organisms.