The Antibiotics in the Chemical Space

Gualtieri, Maxime; Banères-Roquet, Françoise; Villain-Guillot, Philippe; Pugnière, Martine; Leonetti, Jean-Paul

doi:10.2174/092986709787002628

Cited by 18 publications

(12 citation statements)

References 21 publications

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“…Compounds that are in the impermeant region include glycine, phosphate monoanion, lysine, and Na ϩ (Table 3), hydrated ions that indeed would not be expected to cross the bacterial cytoplasmic membrane passively to any great extent. Clinically used antibacterial agents are generally less lipophilic than other drug classes (18,28,29), with the consequence that lipid membrane permeability coefficients are likely to be on the low side, so the permeability coefficient cutoff range of about 10 Ϫ8 cm • s Ϫ1 referred to above is proposed to be a useful medicinal chemistry benchmark for assessment of the passive permeability of bacteria to novel compounds.…”

Section: Resultsmentioning

confidence: 99%

Modeling the Kinetics of the Permeation of Antibacterial Agents into Growing Bacteria and Its Interplay with Efflux

Nichols¹

2017

Antimicrob Agents Chemother

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A mathematical model of the passive permeation of a novel solute into bacteria that explicitly accounts for intracellular dilution through growth was developed. A bacterial cell envelope permeability coefficient of approximately >10 cm · s is predicted to ensure passive permeation into rapidly replicating bacterial cells. The relative importance of the permeability coefficients of the cytoplasmic and outer membranes of Gram-negative bacteria in determining the overall envelope permeability coefficient was analyzed quantitatively. A mathematical description of the balance between passive influx and active efflux was also developed and shows that bacterial expansion through growth can usually be neglected for compounds likely to be prepared in antibacterial drug discovery programs and the balance between passive inward permeation and active outwardly directed efflux predominates. A new parameter, efflux efficiency (η, where η is equal to /, in which is the rate coefficient for the efflux pump and is the permeability coefficient for the membrane across which the pump acts), is introduced, and the consequences for the efficiency of efflux pumping by a single pump, two pumps in parallel across either the cytoplasmic or the outer membrane, and two pumps in series, one across the cytoplasmic membrane and one across the outer membrane of Gram-negative bacteria, are explored. The results, showing additive efficiency for two pumps acting across a single membrane and multiplicative efficiency for two pumps acting in series across the cytoplasmic and outer membranes, can be quantitatively related to the ratios between MICs measured against pump-sufficient and pump deletion strains and agree with those of previous experimental and theoretical studies.

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Section: Resultsmentioning

confidence: 99%

Modeling the Kinetics of the Permeation of Antibacterial Agents into Growing Bacteria and Its Interplay with Efflux

Nichols¹

2017

Antimicrob Agents Chemother

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“…Natural products are rich in oxygen atoms, most often found as alcohols or in heterocycles. 15,16 To facilitate the enrichment of alcohol-containing natural products, we pursued development of a reversible tagging strategy using a silyl-functionalized solid support (Scheme 1). Alcohol immobilization is accomplished by activation of the resin to generate the resin-bound silyl triflate or chloride, followed by addition of the alcohol and triethylamine.…”

Section: Resultsmentioning

confidence: 99%

“…Next, we tested the chemoselectivity of resin 1 by subjecting amine-, thiol-and carboxylic acid-containing compounds (15)(16)(17)(18)(19) to the enrichment protocol. All three functional group classes were captured in moderate to high yields clearly demonstrating that exploration of alternative resin architectures would be required to identify an alcohol-selective reagent.…”

Section: Exploration Of a Silyl-functionalized Resinmentioning

confidence: 99%

Chemoselective enrichment for natural products discovery

2011

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Natural products account for a significant proportion of modern day therapeutic agents. However, the discovery of novel compounds is hindered by the isolation process, which often relies upon extraction and chromatographic separation techniques. These methods, which are dependent upon the physicochemical properties of the compounds, have a limited ability to both purify and concentrate the minor components of a biological extract. We have devised an isolation strategy based upon an orthogonal chemical feature, namely, functional group composition. Development of a functional group-targeted method is expected to achieve exceptional resolution given the large number of distinct moieties present in natural product extracts. Here, we describe the generation of controllably reversible covalent enrichment tags for the chemoselective isolation of alcohol-containing natural products from complex mixtures.

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“…However, the antimicrobial activities of both WTA inhibitors were reduced in the presence of 25% bovine serum. Since these compounds are hydrophobic molecules, they may have a tendency to bind to serum, thereby shifting their MICs (17). Because of this promise, it was of interest to evaluate other characteristics of targocil.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Antimicrobial Activity of Wall Teichoic Acid Biosynthesis Inhibitors against Staphylococcus aureus Isolates

Suzuki

Swoboda

Campbell

et al. 2011

Antimicrob Agents Chemother

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Staphylococcus aureus is the leading cause of invasive and superficial human infections, is increasingly antibiotic resistant, and is therefore the target for the development of new antimicrobials. Compounds (1835F03 and targocil) were recently shown to function as bacteriostatic inhibitors of wall teichoic acid (WTA) biosynthesis in S. aureus. To assess the value of targeting WTA biosynthesis in human infection, it was therefore of interest to verify the involvement of WTA in bacterial binding to human corneal epithelial cells (HCECs) and to assess the activities of inhibitors of WTA biosynthesis against clinical isolates of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) from cases of human keratitis. The 1835F03 MIC 90 s were 8 g/ml for MSSA keratitis isolates and >32 g/ml for MRSA keratitis isolates. The MIC 90 for the analog of 1835F03, targocil, was 2 g/ml for both MRSA and MSSA. Targocil exhibited little toxicity at concentrations near the MIC, with increased toxicity occurring at higher concentrations and with longer exposure times. Targocil activity was moderately sensitive to the presence of serum, but it inhibited extracellular and intracellular bacteria in the presence of HCECs better than vancomycin. Targocil-resistant strains exhibited a significantly reduced ability to adhere to HCECs.

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The Antibiotics in the Chemical Space

Cited by 18 publications

References 21 publications

Modeling the Kinetics of the Permeation of Antibacterial Agents into Growing Bacteria and Its Interplay with Efflux

Modeling the Kinetics of the Permeation of Antibacterial Agents into Growing Bacteria and Its Interplay with Efflux

Chemoselective enrichment for natural products discovery

In Vitro Antimicrobial Activity of Wall Teichoic Acid Biosynthesis Inhibitors against Staphylococcus aureus Isolates

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