Anthracimycin activity against contemporary methicillin-resistant Staphylococcus aureus

Abstract

Anthracimycin is a recently discovered novel marine-derived compound with activity against Bacillus anthracis. We tested anthracimycin against an expanded panel of Staphylococcus aureus strains in vitro and in vivo. All strains of S. aureus tested, including methicillin-sensitive (MSSA), methicillin-resistant (MRSA), and vancomycin-resistant strains of S. aureus were sensitive to anthracimycin at minimum inhibitory concentrations (MIC) of < 0.25 mg/L. Although its post-antibiotic effects were minimal, anthracimycin exhibited potent and rapid bactericidal activity, with a > 4-log kill of USA300 MRSA within 3 hours at 5 times its MIC. At concentrations significantly below the MIC, anthracimycin slowed MRSA growth and potentiated the bactericidal activity of the human cathelicidin, LL-37. The bactericidal activity of anthracimycin was somewhat mitigated in the presence of 20% human serum, and the compound was minimally toxic to human cells, with an IC50 = 70 mg/L against human carcinoma cells. At concentrations near the MIC anthracimycin inhibited S. aureus nucleic acid synthesis as determined by optimized macromolecular synthesis methodology, with inhibition of DNA and RNA synthesis occurring in the absence of DNA intercalation. Anthracimycin at a single dose of 1 or 10 mg/kg was able to protect mice from MRSA-induced mortality in a murine peritonitis model of infection. Anthracimycin provides an interesting new scaffold for future development of a novel MRSA antibiotic.

Component Analysis of Multipurpose Contact Lens Solutions To Enhance Activity against Pseudomonas aeruginosa and Staphylococcus aureus

“…Traditional checkerboard and time-kill assays were performed as previously described (10). Overnight cultures of P. aeruginosa (in LB) and S. aureus (in THB) were grown at 37°C, pelleted, washed twice, and resuspended in phosphatebuffered saline (PBS) to an OD 600 of 0.40.…”

Anthracimycin, a Potent Anthrax Antibiotic from a Marine‐Derived Actinomycete

“…Although somewhat similar in structure to chlorotonil (2), anthracimycin is a potent antibacterial metabolite with potential in the treatment of Grampositive pathogens such as Bacillus anthracis and methicillin-resistant Staphylococcus aureus (MRSA). That the compound shows promising preliminary activity in vivo (MRSA) [7] and that the dichloro derivative 3 has surprising activity against problematic Gram-negative pathogens, suggests that there could be significant potential utility found in this new antibacterial structure class. X-ray drawing of anthracimycin illustrating its absolute configuration.…”

“…While the mechanism of action remains to be fully defined, it has been observed that the compound inhibits DNA/RNA synthesis in metabolic labeling experiments. [7] Follow up gel-based studies demonstrated that the nucleic acid inhibition does not likely occur through DNA intercalation. [7] Despite a large MIC shift in the presence of mouse serum, early in vivo results from MRSA infected CD1 mice showed that 1 provided significant protection (90% survival) at 10 mpK.…”

“…[7] Follow up gel-based studies demonstrated that the nucleic acid inhibition does not likely occur through DNA intercalation. [7] Despite a large MIC shift in the presence of mouse serum, early in vivo results from MRSA infected CD1 mice showed that 1 provided significant protection (90% survival) at 10 mpK. [7] A more thorough examination of the efficacy of 1 in whole animal models will clearly be important.…”

“…[7] Despite a large MIC shift in the presence of mouse serum, early in vivo results from MRSA infected CD1 mice showed that 1 provided significant protection (90% survival) at 10 mpK. [7] A more thorough examination of the efficacy of 1 in whole animal models will clearly be important. [8] To predict the bioactivity impact of chlorination as found in 2, we prepared the analogous dichloro-anthracimycin derivative 3 by treatment of 1 with N-chlorosuccinimide in dichloromethane (see supporting information).…”