MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria

Wang, Xu; Edwards, Rachel L.; Ball, Haley; Johnson, Claire; Haymond, Amanda; Girma, Misgina; Manikkam, Michelle; McKay, Kyle T.; Arnett, Stacy D.; Osbourn, Damon M.; Alvarez, Sophie; Boshoff, Helena I.; Meyers, Marvin J.; Couch, Robin D.; John, Audrey Odom; Dowd, Cynthia S.

doi:10.1021/acs.jmedchem.8b01026

Cited by 30 publications

(45 citation statements)

References 46 publications

(140 reference statements)

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“…Few studies have examined the bioactivity of dehydrofosmidomycin (8,27), possibly due to the challenge of isolating or synthesizing adequate amounts of the compound. Using our streamlined synthesis, we were able to access sufficient quantities of pure dehydrofosmidomycin to allow in vitro inhibition studies of bacterial DXR, revealing it to be a potent inhibitor of E. coli DXR, with IC 50 values slightly lower than fosmidomycin ( Supplementary Fig.…”

Section: Bioactivity Of Dehydrofosmidomycinmentioning

confidence: 99%

Fosmidomycin biosynthesis diverges from related phosphonate natural products

et al. 2019

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Fosmidomycin and related molecules comprise a family of phosphonate natural products with potent antibacterial, antimalarial and herbicidal activities. To understand the biosynthesis of these compounds, we characterized the fosmidomycin producer, Streptomyces lavendulae, using biochemical and genetic approaches. Surprisingly, we were unable to elicit production of fosmidomycin, instead observing the unsaturated derivative dehydrofosmidomycin, which we showed potently inhibits 1-deoxy-D-xylulose 5-phosphate reductoisomerase and has bioactivity against a number of bacteria. The genes required for dehydrofosmidomycin biosynthesis were established by heterologous expression experiments. Bioinformatics analyses, characterization of intermediates, and in vitro biochemistry show that the biosynthetic pathway involves conversion of a two-carbon phosphonate precursor into the unsaturated three-carbon product via a highly unusual rearrangement reaction, catalyzed by the 2-oxoglutarate dependent dioxygenase DfmD. The required genes and biosynthetic pathway for dehydrofosmidomycin differ substantially from that of the related natural product FR-900098, suggesting that the ability to produce these bioactive molecules arose via convergent evolution.

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Section: Bioactivity Of Dehydrofosmidomycinmentioning

confidence: 99%

Fosmidomycin biosynthesis diverges from related phosphonate natural products

et al. 2019

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“…Due to their charged nature, phosphonic acid antibiotics have poor cellular penetration and bioavailability, and serum half-lives are relatively brief(23,25,40). In the ongoing effort to develop new treatments for malaria and tuberculosis by improving upon the drug-like properties of phosphonates, numerous lipophilic ester prodrugs that target DXR have been generated(41–53) Our phosphonate parent compounds (1 and 3) are similar in anti-staphylococcal potency to FSM and FR-900098 (Table 1); however, lipophilic modification of either compound dramatically improves potency (in most cases by 100-fold) against both S. schleiferi and S. pseudintermedius (compare compound 1 to its prodrug, compound 2, and compound 3 to its prodrug, compound 4) (Table 1). As expected, prodrugs 2 and 4 poorly inhibit purified recombinant S. schleiferi DXR in vitro , since cleavage of the prodrug moiety is required for activity (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Potent, specific MEPicides for treatment of zoonotic staphylococci

Edwards¹,

Heueck²,

Lee

et al. 2019

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24Coagulase-positive staphylococci, which frequently colonize the mucosal surfaces of 25 animals, also cause a spectrum of opportunistic infections including skin and soft tissue 26 infections, urinary tract infections, pneumonia, and bacteremia. However, recent 27 45 robustly inhibit DXR in zoonotic staphylococci, and further, DXR represents a 46 promising, druggable target for future development. 3 47 48 Author Summary 49 The proliferation of microbial pathogens resistant to the current pool of antibiotics is a 50 major threat to public health. Drug resistance is pervasive in staphylococci, including 51 several species that can cause serious zoonotic infections in humans. Thus, new 52 antimicrobial agents are urgently need to combat these life-threatening, resistant 53 infections. Here we establish the MEP pathway as a promising new target against 54 zoonotic staphylococci. We determine that fosmidomycin (FSM) selectively targets the 55 isoprenoid biosynthesis pathway in zoonotic staphylococci, and use forward genetics to 56 identify the transporter that facilitates phosphonate antibiotic uptake. Employing this 57 knowledge, we synthesized a series of potent antibacterial prodrugs that circumvent 58 the transporter. Together, these novel prodrug inhibitors represent promising leads for 59 further drug development against zoonotic staphylococci. 60 61 65 zoonotic infections in humans that are clinically indistinguishable from infections with S. 66 aureus including pneumonia, skin and soft tissue infections, hardware infections, and 67 bacteremia(1-5). Newer clinical microbiological techniques, such as mass 68 spectrometry, now readily distinguish S. aureus from zoonotic coagulase-positive

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“…As a result, MEP pathway inhibition is expected to have a high therapeutic index. Indeed, previous work indicates that the MEPicides are nontoxic to human cell lines and are well-tolerated in animal models (IC 50 of compound 2 against HepG2 cells > 100 μM; IC 50 s of compounds 3 and 4 against HepG2 cells > 50 μM [42,53]. Moreover, FSM has been well-tolerated in preclinical and Phase I and II human studies [23][24][25]55,56].…”

Section: Discussionmentioning

confidence: 99%

“…Due to their charged nature, phosphonic acid antibiotics have poor cellular penetration and bioavailability, and serum half-lives are relatively brief [23,25,40]. In the ongoing effort to develop new treatments for malaria and tuberculosis by improving upon the drug-like properties of phosphonates, numerous lipophilic ester prodrugs that target DXR have been generated [41][42][43][44][45][46][47][48][49][50][51][52][53]. Our phosphonate parent compounds (1 and 3) are similar in anti-staphylococcal potency to FSM and FR-900098 (Fig 1 and Table 1); however, lipophilic modification of either compound dramatically improves potency (in most cases by 100-fold) against both S. schleiferi and S. pseudintermedius (compare compound 1 to its prodrug, compound 2, and compound 3 to its prodrug, compound 4) (Fig 1 and Table 1).…”

Section: Lipophilic Ester Prodrugs With Improved Anti-staphylococcal mentioning

confidence: 99%

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Potent, specific MEPicides for treatment of zoonotic staphylococci

et al. 2020

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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 multidrugresistant 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 PLOS PATHOGENS

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MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria

Cited by 30 publications

References 46 publications

Fosmidomycin biosynthesis diverges from related phosphonate natural products

Fosmidomycin biosynthesis diverges from related phosphonate natural products

Potent, specific MEPicides for treatment of zoonotic staphylococci

Potent, specific MEPicides for treatment of zoonotic staphylococci

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