Novel reverse thia-analogs of fosmidomycin: Synthesis and antiplasmodial activity

Fosmidomycin transport through the phosphate‐specific porins OprO and OprP of Pseudomonas aeruginosa

“…We reconstituted OprP and OprO into lipid bilayer membranes to study their interaction with the antibiotic fosmidomycin, which is also used as an anti‐malaria drug based on its effect on the DXP (1‐deoxy‐D‐xylulose 5‐phosphate) reductoisomerase (Lienau et al., 2019; Quinn et al, 2016). All experiments were performed using 0.1 M KCl, 10 mM HEPES pH 7.4 as electrolyte and a neutral lipid to adopt to physiological conditions because high ionic strength and small differences in pH have some influence on channel properties of OprP and OprO (Benz & Hancock, 1987, Benz et al., 1993, Ganguly et al, 2017).…”

“…All experiments performed in presence of fosmidomycin demonstrate a decrease of chloride flux in dependence of fosmidomycin concentration (see Figures 2–4) which suggest, together with the published MD simulations (Golla et al., 2020), that the antibiotic can bind inside and permeate through OprO and OprP in the outer membrane of P. aeruginosa . Fosmidomycin showed already promising results in the treatment of bacterial and plasmodium infections (Lienau et al., 2019; Mine et al., 1980; Quinn et al, 2016). Our data with the ones already present in literature show that phosphonic acid‐containing antibiotics are in general good candidates to treat the infections of P. aeruginosa at the very beginning and through a favorable OM transport system.…”

“…Fosmidomycin inhibits the DXP (1‐deoxy‐D‐xylulose 5‐phosphate) reductoisomerase, a key enzyme in the non‐mevalonate pathway of isoprenoid biosynthesis present in both bacteria and protozoa but not in humans (Kuzuyama et al., 1998; Jomaa et al., 1999; Rohmer et al, 1993). Thus, the molecule has both antibiotic and antimalarial activity (Lienau et al., 2019). In general, this drug seems to be slightly more active against the molecular machinery of Plasmodium falciparum .…”

Inhibition of the Yersinia pestis Methylerythritol Phosphate Pathway of Isoprenoid Biosynthesis by α-Phenyl-Substituted Reverse Fosmidomycin Analogues

“…All assayed compounds were synthesized according to previously described procedures. − The addition of differently substituted phenyl rings at the α-position of fosmidomycin analogues can increase their potency against IspC enzymes from bacteria and the protozoan, Plasmodium falciparum. ,− , However, to our knowledge, no inhibitors from this class have been tested against YpIspC. Furthermore, no crystal structures of YpIspC bound to fosmidomycin or one of its analogues have been resolved.…”

“…The synthesis of the carba analog 1a was performed according to Behrendt et al, 2010 and the carba analogues 2a , 2d , 3a , and 3d according to Behrendt et al, 2011. , The thia analogues 1b , 2b , 3b–c were synthesized following the same procedures described by Kunfermann et al, 2013 and the analogues 4a–b according to Lienau et al, 2019. , The oxa analogues 1c , 2c , 3c , 3f , and 5 were synthesized according to Brücher et al, 2012 and the 3,4 dimethoxy analog, 3g , was synthesized according to Konzuch et al, 2014. , …”