Abstract
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.
Highlights
Marinopyrroles were first reported to show antibiotic activity against methicillin-resistantStaphylococcus aureus (MRSA) several years ago [1]
We reported the first total synthesis of marinopyrrole A along with “symmetrical”
In addition to those symmetrical marinopyrrole derivatives, we envisage that the “asymmetrical” marinopyrrole derivatives shown in Scheme 1 should have different biological activity than their symmetrical counterparts
Summary
Marinopyrroles were first reported to show antibiotic activity against methicillin-resistant. MRSA infections have reached epidemic proportions in many countries [7] and represent the most common cause of skin and soft tissue infections in the United States [8] Both hospital-associated and community-associated MRSA can exhibit broader resistance to multiple classes of antibiotics [7,9,10,11]. Evaluation of the pharmacological properties has revealed that marinopyrrole A has potent concentration-dependent antibacterial activity against clinically-relevant hospital- and community-acquired MRSA strains, a prolonged post-antibiotic effect superior to the first-line current. We report our design and synthesis of novel marinopyrrole derivatives with excellent antibiotic activity against MRSA but only limited serum inactivation
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