Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. (ESKAPE) pathogens can readily develop resistance to the biocidal action of existing antibiotics. Multidrug resistance among these organisms is responsible for many serious infections. Infections by methicillin-resistant Staphylococcus aureus (MRSA) alone cost U.S. hospitals between $3.2 and $4.2 billion annually. Compounding this problem is the propensity of ESKAPE pathogens to form biofilms. To date, no anti-biofilm agents are available for therapeutic use. Thus, it is imperative that we continue to seek new antibiotics for combating both ESKAPE and biofilm infections. We previously reported marinopyrroles and their fragment derivatives − novel pyrrolomycins, as potent anti-MRSA and anti-staphylococcal biofilm agents. Using fragment-based and bioisostere approaches, we designed, synthesized, tested these pyrrolomycins, and performed quantitative structure-activity relationship (QSAR) analysis. In addition, drug metabolism and pharmacokinetics (DMPK) were investigated. The results of these studies revealed that these natural product derivatives have a minimum inhibitory concentration in the nanogram/mL and a minimum bactericidal concentration in the low microgram/mL range against ESKAPE pathogens and biofilms with a lack of mammalian cytotoxicity and without detectable resistance, and the desirable oral bioavailability and pharmacokinetic profiles. This presentation will discuss the development of these novel pyrrolomycins as potent antibacterial agents against ESKAPE pathogens and biofilms, their QSAR, DMPK, and in vivo efficacy in animal models.

Novel pyrrolomycins as potent antibacterial agents against ESKAPE pathogens and biofilms

253rd National Meeting (2017)

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