Abstract
Staphylococcus aureus is an important human pathogen in both hospital and the community that has demonstrated resistance to all currently available antibiotics over the last two decades. Multidrug-resistant isolates of methicillin-resistant S. aureus (MRSA) exhibiting decreased susceptibilities to glycopeptides has also emerged, representing a crucial challenge for antimicrobial therapy and infection control. The availability of complete whole-genome nucleotide sequence data of various strains of S. aureus presents an opportunity to explore novel compounds and their targets to address the challenges presented by antimicrobial drug resistance in this organism. Study compounds α-amyrin [3β-hydroxy-urs-12-en-3-ol (AM)], betulinic acid [3β-hydroxy-20(29)-lupaene-28-oic acid (BA)] and betulinaldehyde [3β-hydroxy-20(29)-lupen-28-al (BE)] belong to pentacyclic triterpenoids and were reported to exhibit antimicrobial activities against bacteria and fungi, including S. aureus. The MIC values of these compounds against a reference strain of methicillin-resistant S. aureus (MRSA) (ATCC 43300) ranged from 64 µg/ml to 512 µg/ml. However, the response mechanisms of S. aureus to these compounds are still poorly understood. The transcription profile of reference strain of MRSA treated with sub-inhibitory concentrations of the three compounds was determined using Affymetrix GeneChips. The findings showed that these compounds regulate multiple desirable targets in cell division, two-component system, ABC transporters, fatty acid biosynthesis, peptidoglycan biosynthesis, aminoacyl-tRNA synthetase, ribosome and β-lactam resistance pathways which could be further explored in the development of therapeutic agents for the treatment of S. aureus infections.
Highlights
Antibiotic resistance is a growing global threat to the effective treatment of infectious diseases
The growth rate of the organism decreased at concentrations K MIC and MIC after 30 min for amyrin [3b-hydroxy-urs-12-en-3-ol (AM); and 45 min for betulinic acid [3b-hydroxy-20(29)-lupaene-28-oic acid (BA) and betulinaldehyde [3b-hydroxy-20(29)-lupen-28-al (BE)
After 300 min, the growth of the organism at K MIC was generally higher than the growth at MIC. These effects of the growth indicates that AM, BA and BE are bacteriostatic compounds as reported by Chung et al [17]
Summary
Antibiotic resistance is a growing global threat to the effective treatment of infectious diseases. Over the past two decades resistance has been reported in many clinically important pathogens and to a broad range of antimicrobials in clinical use today [1,2,3]. This has been the driving force for the discovery of novel agents with antimicrobial activity that may potentially lead to therapeutic agents. Over the past 30 years, only two new classes of antibiotics for the treatment of staphylococcal infections have been introduced: the oxazolidinones represented by linezolid, and the lipopeptide daptomycin [5]. Promising targets for novel antibacterials against S. aureus include cell division, DNA replication and biosynthesis of fatty acid, peptidoglycan and protein [7]
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