Infections caused by drug-resistant pathogens are on the rise. The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains exemplifies the urgent need for new antibiotics. The marine natural product, marinopyrrole A, was previously shown to have potent antibiotic activity against Gram-positive pathogens, including MRSA. However, its minimum inhibitory concentration (MIC) against MRSA was increased by >500 fold in the presence of 20% human serum, thus greatly limiting therapeutic potential. Here we report our discovery of a novel derivative of marinopyrrole A, designated 1a, featuring a 2–4 fold improved MIC against MRSA and significantly less susceptibility to serum inhibition. Importantly, compound 1a displayed rapid and concentration-dependent killing of MRSA. Compared to the natural product counterpart, compound 1a provides an important natural product based scaffold for further Structure Activity Relationship (SAR) and optimization.
References
[1]
Hughes, C.C.; Prieto-Davo, A.; Jensen, P.R.; Fenical, W. The marinopyrroles, antibiotics of an unprecedented structure class from a marine Streptomyces sp. Org. Lett. 2008, 10, 629–631, doi:10.1021/ol702952n. 18205372
[2]
Nicolaou, K.C.; Simmons, N.L.; Chen, J.S.; Haste, N.M.; Nizet, V. Total synthesis and biological evaluation of marinopyrrole A and analogues. Tetrahedron Lett. 2011, 52, 2041–2043, doi:10.1016/j.tetlet.2010.09.059. 21499535
[3]
Hughes, C.C.; Yang, Y.L.; Liu, W.T.; Dorrestein, P.C.; la Clair, J.J.; Fenical, W. Marinopyrrole A target elucidation by acyl dye transfer. J. Am. Chem. Soc. 2009, 131, 12094–12096, doi:10.1021/ja903149u. 19673475
[4]
Hughes, C.C.; Kauffman, C.A.; Jensen, P.R.; Fenical, W. Structures, reactivities, and antibiotic properties of the marinopyrroles A–F. J. Org. Chem. 2010, 75, 3240–3250, doi:10.1021/jo1002054. 20405892
[5]
Kanakis, A.A.; Sarli, V. Total synthesis of (±)-marinopyrrole A via copper-mediated N-arylation. Org. Lett. 2010, 12, 4872–4875, doi:10.1021/ol102035s. 20886840
[6]
Cheng, C.; Pan, L.; Chen, Y.; Song, H.; Qin, Y.; Li, R. Total synthesis of (±)-marinopyrrole a and its library as potential antibiotic and anticancer agents. J. Comb. Chem. 2010, 12, 541–547, doi:10.1021/cc100052j. 20429575
[7]
Grundmann, H.; Aires-de-Sousa, M.; Boyce, J.; Tiemersma, E. Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet 2006, 368, 874–885, doi:10.1016/S0140-6736(06)68853-3. 16950365
[8]
Como-Sabetti, K.; Harriman, K.H.; Buck, J.M.; Glennen, A.; Boxrud, D.J.; Lynfield, R. Community-associated methicillin-resistant Staphylococcus aureus: Trends in case and isolate characteristics from six years of prospective surveillance. Public Health Rep. 2009, 124, 427–435. 19445419
[9]
Chambers, H.F.; Deleo, F.R. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat. Rev. Microbiol. 2009, 7, 629–641, doi:10.1038/nrmicro2200.
Lowy, F.D. Antimicrobial resistance: The example of Staphylococcus aureus. J. Clin. Invest. 2003, 111, 1265–1273. 12727914
[12]
Zhao, K.; Reiner, J.; Xie, W. FDA new drug approvals in 2000. Front. Biotechnol. Pharm. 2001, 2, 329–349.
[13]
Eisenstein, B.I. Lipopeptides, focusing on daptomycin, for the treatment of Gram-positive infections. Expert. Opin. Investig. Drugs 2004, 13, 1159–1169, doi:10.1517/13543784.13.9.1159.
[14]
FDA Approves Teflaro for Bacterial Infections. FDA News Events 29 October 2010, Available online: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm231594.htm (accessed on 1 March 2012).
[15]
Butler, M.S.; Buss, A.D. Natural products—The future scaffolds for novel antibiotics? Biochem. Pharmacol. 2006, 71, 919–929, doi:10.1016/j.bcp.2005.10.012.
[16]
Haste, N.M.; Hughes, C.C.; Tran, D.N.; Fenical, W.; Jensen, P.R.; Nizet, V.; Hensler, M.E. Pharmacological properties of the marine natural product marinopyrrole A against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2011, 55, 3305–3312, doi:10.1128/AAC.01211-10.
[17]
Furneaux, R.H.; Tyler, P.C. Improved Syntheses of 3H,5H-Pyrrolo[3,2-d]pyrimidines. J. Org. Chem. 1999, 64, 8411–8412, doi:10.1021/jo990903e.
[18]
Rochais, C.; Lisowski, V.; Dallemagne, P.; Rault, S. Synthesis and biological evaluation of novel pyrrolopyrrolizinones as anticancer agents. Bioorg. Med. Chem. 2006, 14, 8162–8175, doi:10.1016/j.bmc.2006.09.022. 17011196
[19]
Chin, J.N.; Rybak, M.J.; Cheung, C.M.; Savage, P.B. Antimicrobial activities of ceragenins against clinical isolates of resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2007, 51, 1268–1273, doi:10.1128/AAC.01325-06.
[20]
Credito, K.; Lin, G.; Appelbaum, P.C. Activity of daptomycin alone and in combination with rifampin and gentamicin against Staphylococcus aureus assessed by time-kill methodology. Antimicrob. Agents Chemother. 2007, 51, 1504–1507, doi:10.1128/AAC.01455-06.
[21]
Ueda, Y.; Kanazawa, K.; Eguchi, K.; Takemoto, K.; Eriguchi, Y.; Sunagawa, M. In vitro and in vivo antibacterial activities of SM-216601, a new broad-spectrum parenteral carbapenem. Antimicrob. Agents Chemother. 2005, 49, 4185–4196, doi:10.1128/AAC.49.10.4185-4196.2005.
