Chemical modification of erythromycin antibiotics. 4. Structure-activity relations of erythromycin esters

Yc, Martin; Ph, Jones; Tj, Perun; We, Grundy; Bell, Stephen A.; Rr, Bower; Nl, Shipkowitz

doi:10.1021/jm00276a018

Cited by 27 publications

(9 citation statements)

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“…Second, some of the assumed parameters are quite unrealistic. For example, from the logP value (2.54) and the weakness of its basic group [pKa 8.6] (Martin et al, 1972), the permeability coefficient of erythromycin across IM is expected to be about 1 × 10 −3 cm s −1 following the procedure used by us (Thanassi et al, 1995). Yet the parameter used [0.1 s −1 as the first-order rate constant] (Lovmar et al, 2009) corresponds to the permeability coefficient of 2.3 × 10 −6 cm s −1 , nearly three orders of magnitude lower than the expected value above.…”

Section: The Effect Of Pump Activity In Intact Cellsmentioning

confidence: 99%

Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria

2012

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Antibiotic resistance mechanisms reported in Gram-negative bacteria are producing a worldwide health problem. The continuous dissemination of «multi-drug resistant» (MDR) bacteria drastically reduces the efficacy of our antibiotic “arsenal” and consequently increases the frequency of therapeutic failure. In MDR bacteria, the over-expression of efflux pumps that expel structurally-unrelated drugs contributes to the reduced susceptibility by decreasing the intracellular concentration of antibiotics. During the last decade, several clinical data indicate an increasing involvement of efflux pumps in the emergence and dissemination of resistant Gram-negative bacteria. It is necessary to clearly define the molecular, functional and genetic bases of the efflux pump in order to understand the translocation of antibiotic molecules through the efflux transporter. The recent investigation on the efflux pump AcrB at its structural and physiological level, including the identification of drug affinity sites and kinetic parameters for various antibiotics, may open the way to rationally develop an improved new generation of antibacterial agents as well as efflux inhibitors in order to efficiently combat efflux-based resistance mechanisms.

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Section: The Effect Of Pump Activity In Intact Cellsmentioning

confidence: 99%

Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria

2012

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“…The present work attempts to rectify this situation. Among the compounds considered here, log P values of 2.54 and 2.91 have been noted for erythromycin, and 3.24 13 for clarithromycin. These are similar to the values given in Table .…”

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confidence: 92%

“…1 For QSAR purposes, we converted these values to mmol/L and recorded them as the logarithms of their reciprocals [log(1/ MIC)] in Table 2. log(1/MIC) is the dependent variable in eq 11 below, but it is also an independent variable in eq 12.…”

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confidence: 99%

Quantitative Structure−Activity Relationships among Macrolide Antibacterial Agents: In Vitro and in Vivo Potency against Pasteurella multocida

et al. 1997

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Quantitative structure-activity relationships have been found among macrolide antibacterial agents in their potencies against the bacterial pathogen Pasteurella multocida both in vitro and in mouse infections. To obtain these relationships we measured, among other things, the pK(a)'s and log P's of 15 known macrolides of diverse structures. Among these compounds, in vitro potency [log(1/MIC)] is a function of log P, log D, and CMR (R = 0.86). In vivo potency is a function of the higher pK(a), the HPLC chromatographic capacity factor log k', log(1/MIC) and pNF (R = 0.93). pNF is defined as the negative logarithm of the fraction of neutral drug molecules present in aqueous solution at pH 7.4. The same physical properties were determined for 14 macrolides not used in developing the original QSAR models. Using the in vivo model, we calculated the mouse protection potency ranges for these new compounds. Ten estimates agreed with those observed, three were lower by a half-order of magnitude, and one was calculated to be active in the range of 15-50 mg/kg, but in fact was not active at 50 mg/kg, the highest level tested. When these new compounds were combined with the original 15, and the QSAR's updated, the new equations for the in vitro and in vivo potencies were essentially the same as those originally found. Hence, the physical properties indicated above are major determinants of macrolide antibacterial potencies.

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“…Many commercial medicines contain prodrugs or derivatives of ERY. Instability at the gastric pH, unpleasant taste, and limited solubility in water are the main factors that have prompted the research for alternative derivatives and salts of ERY (4)(5)(6). For instance, erythromycin-A 2′-ethylsuccinate is used as an oral suspension in children to reduce the unpleasant taste of the drug.…”

Section: Introductionmentioning

confidence: 99%

Amphiphilic Erythromycin-Lipoamino Acid Ion Pairs: Characterization and In Vitro Microbiological Evaluation

et al. 2011

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A series of amphiphilic ion pairs of erythromycin (ERY) with lipoamino acids (LAAs) were produced. The ion pairs were prepared by evaporation of a water/ethanol co-solution of the drug and LAA bearing an alkyl side chain of 10-16 carbon atoms. For the sake of comparison, equimolar physical mixtures were prepared by triturating ERY and the LAA in the absence of any solvent. FTIR spectroscopy confirmed the structure of ion pairs, while differential scanning calorimetry and powder X-ray diffractometry were used to assess the formation of new saline species. The solubility pattern of the coevaporates in different aqueous and organic solvents confirmed their amphiphilic properties. ERY-LAA ion pairs were submitted to an in vitro microbiological assay against different bacterial strains, both susceptible and resistant to macrolides. The presence of the LAA moiety was shown not altering the antibacterial spectrum of activity of the drug. These results can be the basis for a further evaluation of ERY-LAA ion pairs as a mean to improve the penetration of the drug inside bacterial cells and to optimize the loading of ERY in lipid-based nanocarriers.

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Chemical modification of erythromycin antibiotics. 4. Structure-activity relations of erythromycin esters

Cited by 27 publications

References 0 publications

Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria

Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria

Quantitative Structure−Activity Relationships among Macrolide Antibacterial Agents: In Vitro and in Vivo Potency against Pasteurella multocida

Amphiphilic Erythromycin-Lipoamino Acid Ion Pairs: Characterization and In Vitro Microbiological Evaluation

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