Abstract
The acronymously named “ESKAPE” pathogens represent a group of bacteria that continue to pose a serious threat to human health, not only due to their propensity for repeated emergence, but also due to their ability to “eskape” antibiotic treatment1,2. The evolution of multi-drug resistance in these pathogens alone has greatly outpaced the development of new therapeutics, necessitating an alternative strategy for antibiotic development that considers the evolutionary mechanisms driving antibiotic resistance. In this study, we synthesize a novel inorganic antibiotic, phosphopyricin, which has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). We show that this potent antibiotic is bactericidal, and exhibits low toxicity in an acute dose assay in mice. As a synthetic compound that does not occur naturally, phosphopyricin would be evolutionarily foreign to microbes, thereby slowing the evolution of resistance. In addition, it loses antibiotic activity upon exposure to light, meaning that the active antibiotic will not accumulate in the general environment where strong selective pressures imposed by antibiotic residuals are known to accelerate resistance. Phosphopyricin represents an innovation in antimicrobials, having a synthetic core, and a photosensitive chemical architecture that would reduce accumulation in the environment.
Highlights
Antibiotics have been synthesized previously, including fosfomycin[9], clindamycin[10], and torezolid[11]; these molecules are organophosphates that may be susceptible to existing antibiotic resistance mechanisms
We identified one compound that has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE), and subsequently carried out systematic replacement of its chemical side groups to increase its potency
To identify features of 9bWC2 that were essential for antimicrobial activity, we systematically varied chemical side groups, beginning with substitution of the C2-bound pyrrole with C2-bound thiophene, which resulted in loss of antimicrobial activity against S. aureus (11bW, minimum inhibitory concentration (MIC) > 1024 μg/mL) (Fig. 1)
Summary
Antibiotics have been synthesized previously, including fosfomycin[9], clindamycin[10], and torezolid[11]; these molecules are organophosphates that may be susceptible to existing antibiotic resistance mechanisms. We identified one compound that has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE), and subsequently carried out systematic replacement of its chemical side groups to increase its potency. We show that the resulting compound, called phosphopyricin, is bactericidal, exhibits low toxicity in mice, and loses activity when exposed to light.
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