ABSTRACT
Antimicrobial resistance constitutes a global health problem, while the discovery and development of novel antibiotics is stagnating. Methicillin-resistant Staphylococcus aureus, responsible for the establishment of recalcitrant, biofilm-related infections, is a well-known and notorious example of a highly resistant micro-organism. Since resistance development is unavoidable with conventional antibiotics that target bacterial viability, it is vital to develop alternative treatment options on top. Strategies aimed at more subtle manipulation of bacterial behavior have recently attracted attention. Here, we provide a literature overview of several small-molecule potentiators for antibiotics, identified for the treatment of Staphylococcus aureus infection. Typically, these potentiators are not bactericidal by themselves and function by reversing resistance mechanisms, by attenuating Staphylococcus aureus virulence, and/or by interfering with quorum sensing.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/pharmacokinetics , Methicillin-Resistant Staphylococcus aureus/drug effects , Staphylococcal Infections/drug therapy , Animals , Drug Resistance, Bacterial , Drug Synergism , Humans , Methicillin-Resistant Staphylococcus aureus/pathogenicity , Quorum Sensing/drug effects , Staphylococcal Infections/microbiologyABSTRACT
A library of 52 hamamelitannin analogues was synthesized and investigated for its ability to potentiate the effect of vancomycin toward Staphylococcus aureus biofilms. Several compounds were found to effectively increase the susceptibility of staphylococcal biofilms toward this glycopeptide. The most active analogue identified in this study showed an EC50 value of 0.26 µM.
ABSTRACT
Antimicrobial research is increasingly being focused on the problem of resistance and biofilm formation. Hamamelitannin (HAM) was recently identified as an antimicrobial potentiator for conventional antibiotics towards Staphylococcus aureus. This paper describes the synthesis and biological evaluation of novel hamamelitannin analogues with alternative central scaffolds. Via a ligand-based approach, several interesting compounds with improved synthetic accessibility were identified as potentiators for vancomycin in the treatment of MRSA infections.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Drug Design , Gallic Acid/analogs & derivatives , Hexoses/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/physiology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Drug Evaluation, Preclinical , Gallic Acid/chemical synthesis , Gallic Acid/chemistry , Gallic Acid/pharmacology , Hexoses/chemical synthesis , Hexoses/chemistry , Ligands , Microbial Sensitivity Tests , User-Computer InterfaceABSTRACT
Staphylococcus aureus is a frequent cause of biofilm-related infections. Bacterial cells within a biofilm are protected from attack by the immune system and conventional antibiotics often fail to penetrate the biofilm matrix. The discovery of hamamelitannin as a potentiator for antibiotics, recently led to the design of a more drug-like lead. In the present study, we want to gain further insight into the structure-activity relationship (S.A.R.) of the 5-position of the molecule, by preparing a library of 21 hamamelitannin analogues.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Gallic Acid/analogs & derivatives , Hexoses/chemistry , Hexoses/pharmacology , Staphylococcus aureus/drug effects , Vancomycin/pharmacology , Drug Design , Gallic Acid/chemistry , Gallic Acid/pharmacology , Humans , Microbial Sensitivity Tests , Quorum Sensing/drug effects , Staphylococcal Infections/drug therapy , Staphylococcus aureus/physiology , Structure-Activity RelationshipABSTRACT
The modulation of bacterial communication to potentiate the effect of existing antimicrobial drugs is a promising alternative to the development of novel antibiotics. In the present study, we synthesized 58 analogues of hamamelitannin (HAM), a quorum sensing inhibitor and antimicrobial potentiator. These efforts resulted in the identification of an analogue that increases the susceptibility of Staphylococcus aureus towards antibiotics inâ vitro, in Caenorhabditis elegans, and in a mouse mammary gland infection model, without showing cytotoxicity.
Subject(s)
Anti-Bacterial Agents/pharmacology , Gallic Acid/analogs & derivatives , Hexoses/pharmacology , Quorum Sensing/drug effects , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Gallic Acid/chemistry , Gallic Acid/pharmacology , Hexoses/chemistry , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
Treatment of Staphylococcus aureus infections has become increasingly challenging due to the rapid emergence and dissemination of methicillin-resistant strains. In addition, S. aureus reside within biofilms at the site of infection. Few novel antibacterial agents have been developed in recent years and their bacteriostatic or bactericidal activity results in selective pressure, inevitably inducing antimicrobial resistance. Consequently, innovative antimicrobials with other modes of action are urgently needed. One alternative approach is targeting the bacterial quorum sensing (QS) system. Hamamelitannin (2',5-di-O-galloyl-d-hamamelose; HAM) was previously suggested to block QS through the TraP QS system and was shown to increase S. aureus biofilm susceptibility towards vancomycin (VAN) although mechanistic insights are still lacking. In the present study we provide evidence that HAM specifically affects S. aureus biofilm susceptibility through the TraP receptor by affecting cell wall synthesis and extracellular DNA release of S. aureus. We further provide evidence that HAM can increase the susceptibility of S. aureus biofilms towards different classes of antibiotics in vitro. Finally, we show that HAM increases the susceptibility of S. aureus to antibiotic treatment in in vivo Caenorhabditis elegans and mouse mammary gland infection models.