Combinatorial modification of natural products: synthesis and in vitro analysis of derivatives of thiazole peptide antibiotic GE2270 A: A-ring modifications

Abstract Thiazole peptide GE2270 A ( 1 ) possesses potent antimicrobial activity against many gram-positive pathogens, including methicillin resistant Staphylococcus aureus ( S. aureus, MRSA; MIC 90 =0.06 μg/mL) and vancomycin resistant Enterococcus spp . (VRE; MIC 90 =0.03 μg/mL); however its poor aqueous solubility has prohibited its development for the clinical treatment of infections. An integrated combinatorial and medicinal chemistry program was employed to identify derivatives of 1 that retain activity but possess greatly enhanced aqueous solubility.