Closthioamide- a new, unusual natural product with potent antibiotic activity against MRSA
Resistance of gram-positive pathogens against antibiotics is an increasing problem. One of the most problematic gram-positive bacterium in public health is the methicillin-resistant Staphylococcus aureus (MRSA), because it can only be treated with vancomycin and teicoplanin as it is resistant to all other antibiotics in clinical use. Various strains, however, have developed resistance against vancomycin as well. In addition, vancomycin-resistant enterococci (VRE) are one of the most important causes of nosocomial infections. As vancomycin-resistance is often accompanied by multi-drug resistance, there are no antibiotics available to treat such VRE-infections to date.
The invention discloses closthioamide, a novel type of antibiotics representing a fully unprecedented polythioamide natural product.
Closthioamide is the first secondary metabolite isolated from strictly anaerobic bacteria, specifically Clostridium cellulolyticum. This unique compound is only moderately cytotoxic (against HeLa cells), but is highly active against pathogenic, methicillin-resistant Staphylococcus aureus (MRSA) strains as well as against vancomycin-resistant enterococci (VRE) with MIC50 of 0.58 µM. Closthioamide is thus significantly more potent against these bacteria than ciprofloxacin, the standard drug used against VRE, with a remarkable strain selectivity. Closthioamide is a potent inhibitor of bacterial DNA gyrase; however, its molecular mechanism differs from that of the quinolones and aminocoumarins.
In-licensing or cooperation for further development of an antibiotic.
In vitro assays with a panel of pathogens and cell lines conducted. SAR studies ongoing, new derivatives synthezied. PK studies in mice conducted.
Priority filed in October 2009. International application filed in 2010 (WO 2011 050994). US patent (US 8,673980) and European patent granted (EP2493851 B1).
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