Fabl inhibitors

In addition to its broad-spectrum biocidal activity, triclosan (22) displays reversible inhibition of E. coli Fabl with a picomolar K, for binding the enzyme-cofactor complex [4]. Triclosan entry results in the reordering of a loop of amino acids close to the active site, making it a slow, tight-binding inhibitor [41]. 

NB2001 (23), a prodrug of triclosan, has been developed based on the enzyme-catalyzed therapeutic activation (ECTA) concept. Evidence supporting ring opening of the cephalosporin moiety by penicillin-binding proteins and/ or (3-lactamases to release triclosan at the bacterium site, as well as sub-pg/mL MIC on [3-lactamase-positive strains, demonstrates the potential of this approach [42]. 

Several academic and pharmaceutical groups have conducted structure-based design and SAR studies around triclosan aiming at harvesting its potency without its biocidal component. Among the results of these efforts, CPP (24) was found to be sevenfold more tightly bound to E. coli Fabl than triclosan with an MIC value of 0.07 pg/mL, fourfold lower than that of triclosan [43]. Phenoxyphenol 25 is extremely potent 

---

Hevener KE, Mehboob S, Su P-C, Truong K, Boci T, Deng J, GhassemiM, Cook JL, Johnson ME (2011) Discovery of a novel and potent class of F. Tularensis enoyl-reductase (fabl) inhibitors by molecular shape and electrostatic matching. J Med Chem 55 268-279... 

A few natural products, mostly polyphenols and fatty acids, are low micromolar inhibitors of Fabl. Based on a different template, (E)-oroidin (33) displays an uncompetitive binding mechanism, similar to the one observed for triclosan [54]. 

Among the few reported inhibitors, the optimized HTS lead phe-nylimidazole 39 is an interesting candidate against S. pneumoniae with nanomolar FabK inhibition and an MIC90 of 4 pg/mL [59]. The same team hybridized 29, a FabI pyridine inhibitor with 39 to provide 40, in an attempt to realize a compound with a dual mode of action. Although inhibition of both enzymes as well as sub-pg/ mL MIC against S. pneumoniae is retained, the Fabl-related antibacterial activity against S. aureus is lost [60]. 

The last step in the fatty acid biosynthetic pathway is catalyzed by enoyl-acyl carrier protein (ACP) reductase, which is responsible for reduction of the double bond in the enoyl-ACP derivative (Heath and Rock, 1995 Payne et al., 2002). While fabl genes encode enoyl-ACP reductases (FabI enzymes) in S. aureus and E. coli, an alternative enoyl-ACP reductase, FabK, replaces the function of Fabl in a number of bacterial species such as Streptococcus pneumoniae (Heath and Rock, 2000). More interestingly, a number of bacterial species (such as Enterococcus faecalis and Pseudomonas aeruginosa) possess both the Fabl and FabK enzymes (Heath and Rock, 2000). To discover Fabl-specific antibacterial inhibitors, Payne and colleagues at GlaxoSmithKline (GSK) developed assays for various versions of enoyl-ACP reductases (Payne et al., 2002 Seefeld et al., 2003) based on the following reaction scheme ... 

Typical applications of zeolite membranes in reactors include i) conversion enhancement either by equilibrium displacement (product removal) or by removal of catalyst poisons/ inhibitors and ii) selectivity enhancement either by control of residence time or by control of reactant traffic. A large number of examples are reported and discussed in [49,50,52], Several of them are reported in fable 3. The use of a zeolite membrane as a distributor for a reactant has been attempted for the partial oxidation of alkanes such as propane to propene [137], or n-butane to maleic anhydride [138]. Limited performances were obtained because the back-diffusion of the alkane is hardly controllable with this type of microporous membrane [139]. 

---