Abstract
BackgroundWe evaluated the in vitro activity of a merochlorin A, a novel compound with a unique carbon skeleton, against a spectrum of clinically relevant bacterial pathogens and against previously characterized clinical and laboratory Staphylococcus aureus isolates with resistance to numerous antibiotics.MethodsMerochlorin A was isolated and purified from a marine-derived actinomycete strain CNH189. Susceptibility testing for merochlorin A was performed against previously characterized human pathogens using broth microdilution and agar dilution methods. Cytotoxicity was assayed in tissue culture assays at 24 and 72 hours against human HeLa and mouse sarcoma L929 cell lines.ResultsThe structure of as new antibiotic, merochlorin A, was assigned by comprehensive spectroscopic analysis. Merochlorin A demonstrated in vitro activity against Gram-positive bacteria, including Clostridium dificile, but not against Gram negative bacteria. In S. aureus, susceptibility was not affected by ribosomal mutations conferring linezolid resistance, mutations in dlt or mprF conferring resistance to daptomycin, accessory gene regulator knockout mutations, or the development of the vancomycin-intermediate resistant phenotype. Merochlorin A demonstrated rapid bactericidal activity against MRSA. Activity was lost in the presence of 20% serum.ConclusionsThe unique meroterpenoid, merochlorin A demonstrated excellent in vitro activity against S. aureus and C. dificile and did not show cross-resistance to contemporary antibiotics against Gram positive organisms. The activity was, however, markedly reduced in 20% human serum. Future directions for this compound may include evaluation for topical use, coating biomedical devices, or the pursuit of chemically modified derivatives of this compound that retain activity in the presence of serum.
Highlights
The constant evolution of bacterial pathogens with resistance to clinically available antimicrobial agents drives a continuous demand for the development of novel antimicrobial agents
methicillin-resistant S. aureus (MRSA) is endemic in most hospitals, and invasive MRSA infections have been associated with higher mortality rates than comparable infections caused by methicillin-susceptible S. aureus (MSSA), even when adjusting for host factors, with mortality estimates of about 20% for bacteremia [3]
We have examined the in vitro properties of a novel meroterpenoid, merochlorin A (Figure 1), against MSSA and MRSA with a wide range of resistance determinants against most currently available anti-staphylococcal antibiotics
Summary
The constant evolution of bacterial pathogens with resistance to clinically available antimicrobial agents drives a continuous demand for the development of novel antimicrobial agents. In the United States, Staphylococcus aureus is the leading cause of hospital-associated and community-associated bacterial infections involving the bloodstream, skin and soft tissue and other sites, with a the majority of these pathogens being methicillin-resistant S. aureus (MRSA) [1,2]. S. aureus has historically demonstrated a propensity to develop resistance to antibiotics quite rapidly after they are introduced clinically, frequently within 1–2 years [5]. In this setting, the development of novel antimicrobial agents against MRSA continues to be in great demand. We evaluated the in vitro activity of a merochlorin A, a novel compound with a unique carbon skeleton, against a spectrum of clinically relevant bacterial pathogens and against previously characterized clinical and laboratory Staphylococcus aureus isolates with resistance to numerous antibiotics
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