SF3: Unusual Antimicrobial Hexapeptides from a Streptomyces sp. Strain

Antibiotics represent a special class of therapeutic drugs whose abuse affects the entire community. Antibiotic resistance is inevitable and therefore there is a continuous need to identify new lead antimicrobials with novel mechanisms of action [1]. Microorganisms such as actinomycetes and myxobacteria are perfect candidates for antibiotic drug discovery programs because of their capability to synthesize a plethora of small molecules with fascinating chemical structures and potent biological properties. As a part of an ongoing collaboration between Fraunhofer IME and Sanofi, we screened 16,234 microbial extracts against opportunistic microbial pathogens. To this respect, we identified a crude fermentation extract from a Streptomyces sp. strain that showed activity against Mycobacterium smegmatis (as a surrogate strain for M. tuberculosis), methicillin-resistant Staphylococcus aureus (MRSA), and Eschericia coli. Bio-assay guided fractionation led to the isolation of six new halogenated cyclopeptides, SF3 A-C, and SF3 H-I, and three linear chlorinated derivatives, SF3 D-E. Their structures were determined using extensive 2D NMR and HR-MS/MS techniques together with Marfey's analysis. SF3 A-I are piperazic acid-containing peptides characterized by the presence of the novel δ-methylpiperazic acid, the rare 2,3,4,5-tetrahydro-4,5-dihydroxypyridazine-3-carboxylic acid and γ-chloropiperazic acid. The antibacterial activity was traced to the cyclic depsipeptides SF3 A and C that inhibited the growth of M. smegmatis and MRSA at low micromolar concentrations. Interestingly, their linear counterparts were inactive. SF3 A and C are currently being tested against M. tuberculosis. In summary, the finding of a new molecular framework with antibacterial activity demonstrates once more the importance of microbial natural products in anti-infective drug discovery programs.

Keywords: Antibacterial, Mycobacterium smegmatis, MRSA, Peptides.

Reference:

[1] Walsh CT, Wencewickz TA. Prospects for new antibiotics: a molecule-centered perspective. J Antibiot 2014; 67: 7 – 22