Pharmacological Properties of the Marine Natural Product Marinopyrrole A against Methicillin-Resistant Staphylococcus aureus

Abstract

The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains in hospital and community settings presents a great challenge to public health and illustrates the urgency of discovering new antibiotics. Marinopyrrole A is a member of a structurally novel class of compounds identified from a species of marine-derived streptomycetes with evidence of antistaphylococcal activity. We show that marinopyrrole A has potent concentration-dependent bactericidal activity against clinically relevant hospital-and communityacquired MRSA strains, a prolonged postantibiotic effect superior to that of the current first-line agents vancomycin and linezolid, and a favorable resistance profile. Marinopyrrole A showed limited toxicity to mammalian cell lines (at >20؋ MIC). However, its antibiotic activity against MRSA was effectively neutralized by 20% human serum. A variety of marinopyrrole analogs were isolated from culture or synthetically produced to try to overcome the inhibitory effect of serum. While many of these compounds retained potent bactericidal effect against MRSA, their activities were also inhibited by serum. Marinopyrrole A has significant affinity for plastic and may therefore have potential as a potent anti-MRSA agent in cutaneous, intracatheter, or antibiotic-lock applications.

A twist of nature – the significance of atropisomers in biological systems

“…63 Further investigation showed (M)-28 had inhibitory activity against a wide range of MRSA strains and other gram-positive bacteria, as well as against the gram-negative Haemophilus influenza. 73 However, it was found that the therapeutic window for 28 is possibly too narrow for effective treatment, and that it is inactivated by human serum, thus potentially only be applicable in vivo as a topical agent. 73 That marinopyrrole A has shown a high affinity for binding to plastic indicates a potential use as a medical instrument coating agent to prevent infection, with the added bonus of lowered systemic toxicity from the aforementioned serum inactivation.…”

“…73 However, it was found that the therapeutic window for 28 is possibly too narrow for effective treatment, and that it is inactivated by human serum, thus potentially only be applicable in vivo as a topical agent. 73 That marinopyrrole A has shown a high affinity for binding to plastic indicates a potential use as a medical instrument coating agent to prevent infection, with the added bonus of lowered systemic toxicity from the aforementioned serum inactivation. 61 However, chlorinated and fluorinated derivatives have been generated exhibiting comparable MRSA inhibition and some resistance to serum inactivation, and thus may have future applications.…”

Small molecule Mcl-1 inhibitors for the treatment of cancer

“…(Haste, et al, 2011; Hughes, et al, 2009; Nicolaou, et al, 2011) Marinopyrrole A, which was named Maritoclax, was found to also selectively bind to Mcl-1 (IC 50 = 10.1 µM, Bim-BH3, ELISA), decrease Mcl-1 protein levels via proteasomal degradation and induce apoptosis in Mcl-1-dependent, but not Bcl-2- and Bcl-X L -dependent, leukemia(Doi, et al, 2012) and melanoma cells(Pandey, et al, 2013). However, Eichhorn and coworkers disclosed that marinopyrrole A was equally effective against Bcl-2-dependent leukemia cells compared to Mcl-1-dependent cells, and that treatment with marinopyrrole A had no effect upon Mcl-1 expression levels.…”

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

“…(8). Bacterial viability was determined using an optical plate reader (at an optical density at 600 nm [OD 600 ]) and resazurin indicator dye as previously described (9).…”