Antibacterial and antitubercular activity of fosmidomycin, FR900098, and their lipophilic analogs

Abstract

The nonmevalonate pathway (NMP) of isoprene biosynthesis is an exciting new route toward novel antibiotic development. Inhibitors against several enzymes in this pathway are currently under examination. A significant liability of many of these agents is poor cell penetration. To overcome and improve our understanding of this problem, we have synthesized a series of lipophilic, prodrug analogs of fosmidomycin and FR900098, inhibitors of the NMP enzyme Dxr. Several of these compounds show improved antibacterial activity against a panel of organisms relative to the parent compound, including activity against Mycobacterium tuberculosis (Mtb). Our results show that this strategy can be an effective way for improving whole cell activity of NMP inhibitors.

Mechanism and inhibition of 1-deoxy-d-xylulose-5-phosphate reductoisomerase

“…These inhibitors are effective against the growth of malaria-causing P. falciparum in vitro and in vivo (Table 3) [94], and fosmidomycin has shown clinical success in clearing malarial infections in combination with clindamycin [95]. Unfortunately, both compounds have poor bioavailability and do not exhibit antitubercular activity [79,96]. Uptake studies have confirmed that unlike with Gram-negative bacteria, fosmidomycin does not accumulate intracellularly in M. tuberculosis [97].…”

“…9A), a natural antibiotic isolated from the actinobacterium Streptomyces lavendualae [77]. Several reviews provide comprehensive background on the design, synthesis, and biological evaluation of fosmidomycin analogues [26,78,79]. Here, we focus on the kinetics and thermodynamics of interactions between DXR and fosmidomycin.…”

“…One of the reasons underlying the poor pharmacokinetics of fosmidomycin is its polar, anionic character, hindering transport through the lipid-rich mycobacterial cell wall or the several membranes leading to the plasmodial apicoplast, the organelle containing the enzyme. Three inhibitor-design strategies aimed to increase the inhibitor's hydrophobicity include (1) esterified prodrugs that undergo conversion to the intact form of fosmidomycin inside the cell [79,98], (2) introduction of lipophilic moieties onto the backbone of fosmidomycin [87,98,99], and (3) replacement of the phosphonate dianion moiety by lipophilic groups [87,100]. Esterification has shown to be the most successful of these approaches to date in improving antimicrobial efficacy [79,98].…”

The cell envelope glycoconjugates ofMycobacterium tuberculosis

“…Fosmidomycin, which is currently in clinical trials for the treatment of malaria in humans, is a competitive inhibitor of the second enzyme of the pathway, 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR, IspC). Promising results on Mtb were obtained with lipophilic prodrug derivatives of this compound (Uh et al ., 2011) and the availability of several crystal structures of the Mtb DXR enzyme and DXR-fosmidomycin complexes has opened the way to the structure-based design of more potent analogs. Finally, another approach to targeting PG metabolism has focused on inhibiting the Ser/Thr kinases involved in the regulation of this pathway (Molle and Kremer, 2010; Mir et al ., 2011; Gee et al ., 2012).…”

Synthesis, Antibacterial and Antitubercular Evaluation of Cardanol and Glycerol‑Based β-Amino Alcohol Derivatives

“…Considering these significant characteristics of renewable materials such as cardanol and glycerol as well as ample biological activities of lipophilic β-amino alcohols, our research group aims to combine their properties into single compounds with their unique qualities. Lipophilic character of some antibiotic has a significant influence on the antibacterial activity, [56][57][58] which prompted us to the design of new biologically active molecules. Herein we report a new strategy for the synthesis of β-amino alcohols by reacting cardanol epoxide with diverse amines (aliphatic/ aromatic) under catalyst-free and mild conditions in which ethanol is used as the reaction medium.…”