Abstract
Coagulase-positive staphylococci, which frequently colonize the mucosal surfaces of animals, also cause a spectrum of opportunistic infections including skin and soft tissue infections, urinary tract infections, pneumonia, and bacteremia. However, recent advances in bacterial identification have revealed that these common veterinary pathogens are in fact zoonoses that cause serious infections in human patients. The global spread of multidrug-resistant zoonotic staphylococci, in particular the emergence of methicillin-resistant organisms, is now a serious threat to both animal and human welfare. Accordingly, new therapeutic targets that can be exploited to combat staphylococcal infections are urgently needed. Enzymes of the methylerythritol phosphate pathway (MEP) of isoprenoid biosynthesis represent potential targets for treating zoonotic staphylococci. Here we demonstrate that fosmidomycin (FSM) inhibits the first step of the isoprenoid biosynthetic pathway catalyzed by deoxyxylulose phosphate reductoisomerase (DXR) in staphylococci. In addition, we have both enzymatically and structurally determined the mechanism by which FSM elicits its effect. Using a forward genetic screen, the glycerol-3-phosphate transporter GlpT that facilitates FSM uptake was identified in two zoonotic staphylococci, Staphylococcus schleiferi and Staphylococcus pseudintermedius. A series of lipophilic ester prodrugs (termed MEPicides) structurally related to FSM were synthesized, and data indicate that the presence of the prodrug moiety not only substantially increased potency of the inhibitors against staphylococci but also bypassed the need for GlpT-mediated cellular transport. Collectively, our data indicate that the prodrug MEPicides selectively and robustly inhibit DXR in zoonotic staphylococci, and further, that DXR represents a promising, druggable target for future development.
Highlights
Coagulase-positive staphylococci, such as S. pseudintermedius and S. schleiferi subsp. coagulans, are leading causes of skin, soft tissue, and invasive infections in companion animals such as dogs and cats
We determine that fosmidomycin (FSM) selectively targets the isoprenoid biosynthesis pathway in zoonotic staphylococci and use forward genetics to identify the transporter that facilitates phosphonate antibiotic uptake
Two distinct and independent pathways for isoprenoid biosynthesis have evolved, the mevalonate pathway and a mevalonate-independent route that proceeds through methylerythritol phosphate, called the MEP pathway[11]
Summary
Coagulase-positive staphylococci, such as S. pseudintermedius and S. schleiferi subsp. coagulans, are leading causes of skin, soft tissue, and invasive infections in companion animals such as dogs and cats. Coagulans, are leading causes of skin, soft tissue, and invasive infections in companion animals such as dogs and cats These organisms cause zoonotic infections in humans that are clinically indistinguishable from infections with S. aureus including pneumonia, skin and soft tissue infections, hardware infections, and bacteremia[1,2,3,4,5]. Newer clinical microbiological techniques, such as mass spectrometry, readily distinguish S. aureus from zoonotic coagulase-positive staphylococci, which were previously often misidentified[3,6,7]. Primate-associated staphylococcal lineages, including S. aureus, possess the mevalonate pathway, and evidence suggests that mevalonate pathway activity is required for peptidoglycan synthesis, growth, and virulence[12,13,14]. Nonprimate-associated staphylococcal species, including S. pseudintermedius and S. schleiferi, utilize the MEP pathway for isoprenoid biosynthesis[15]. New chemical inhibitors of MEP pathway enzymes hold promise as effective antimicrobials that may provide a high margin of safety
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