Antibiotic Optimization and Chemical Structure Stabilization of Thiomuracin A

Abstract

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of 1 included removing the C2-C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to 1. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of 2, a structurally simplified and chemically stable analogue of 1 which retained potent antibiotic activity.

The posttranslational modification cascade to the thiopeptide berninamycin generates linear forms and altered macrocyclic scaffolds

“…This finding could be explained by the presence of two lantipeptide dehydratases in the berninamycin gene cluster, BerB and -C. One of the enzymes may carry out the phosphorylation/elimination sequence at several serines and Thr 4 , whereas the other dehydratase may subsequently act on the remaining unmodified residues. In one scenario, one dehydratase might process Ser 1,6,8,[10][11][14][15][16] and Thr 4 in an N-to-C direction, whereas the other may be dedicated to reaction at Ser 13 (SI Appendix, Fig. S6).…”

“…They can be classified into subgroups by several criteria, including the size of the macrocyclic ring(s), the oxidation state and substitution pattern of the central pyridine core, and also by the nature of the target in susceptible bacteria. These antibiotics are effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and function by disrupting one of two steps in bacterial protein biosynthesis: (i) blockade of elongation factor binding to the 50S ribosomal subunit (9)(10)(11) or (ii) by binding to the conditional GTPase elongation factor Tu (EF-Tu) and inhibiting its aminoacyl-tRNA chaperone activity (12)(13)(14)(15). There are crystal structures of thiostrepton or nosiheptide bound to the 50S ribosomal subunit (10) and of GE2270 bound to EF-Tu (12), giving detailed information about interactions of these constrained antibiotic scaffolds with their respective targets.…”

Targeting Antibiotic Resistance

“…In 2012, the same group reported the synthesis of a novel derivative of thiomuracin A ( 18 ), termed NVP‐LDU796 ( 19 ), which retains antibacterial activity and shows improved chemical stability and physiochemical properties (Figure 14). 87 Key modifications include removal of the C2–C10 side chain and conversion of the C84 epoxide into an N70–C84 pyrrolidine ring. In co‐crystal structures of NVP‐LDU796 ( 19 ) with EF‐Tu, the conformation adopted is very similar to the those of GE2270 A and LFF571, with key interactions still present (PDB ID: 4G5G) 87…”

Natural products as probes in pharmaceutical research

“…Residue 275 is located within EF-Tu domain II, the binding site for the thiopeptide antibiotic GE2270A [41]. A lead optimization program was initiated using the thiopeptides GE2270A and thiomuracin as starting points [33,34]. Like GE2270 A and thiomuracin, the clinical candidate LFF571 has antimicrobial activity against a range of Gram-positive bacteria, including Clostridium difficile with MIC 90 values between 0.125 and 0.5 µg/ml [35].…”