Repromicin Derivatives with Potent Antibacterial Activity against <i>Pasteurella multocida</i>

McFarland, James W.; Hecker, Scott J.; Jaynes, Burton H.; Jefson, Martin R.; Lundy, Kristin M.; Vu, Chi B.; Glazer, E. A.; Froshauer, S; Hayashi, Shigeru; Kamicker, Barbara J.; Reese, Catherine P.; Ja, Olson

doi:10.1021/jm960435q

Cited by 11 publications

(15 citation statements)

References 7 publications

(11 reference statements)

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“…Finally, it is gratifying to see that log k′ remains a significant descriptor; this was the first physical property we discovered to be associated with in vivo potency among macrolides. 1 To confirm these results, we used eq 12 to calculate the in vivo potency classes of 14 16-membered ring macrolides for which we had the requisite data. The macrolides are the repromicin and desmycosin derivatives shown in Table 5 and are numbered the same as they were when originally reported.…”

Section: T H Imentioning

confidence: 99%

“…This discovery was facilitated by the observation that common macrolides are active in vivo only when they do not exceed a specific degree of lipophilicity as estimated by HPLC methods. 1 Because macrolides are basic substances, it seemed likely that their pK a 's would also influence in vivo activity. To pursue this idea further, we measured the pK a 's, log P's, and the HPLC chromatographic capacity factors (log k's) of 15 known antibacterial macrolides (see Table 1).…”

mentioning

confidence: 99%

“…The in vitro potencies of macrolides against P. multocida are expressed as minimum inhibitory concentrations (MIC's) in µg/mL and were determined as described previously. 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.…”

mentioning

confidence: 99%

“…The in vivo potencies of the macrolides are expressed as PD 50 's, the dose in mg/kg that protects 50% of mice against a lethal challenge of P. multocida. 1 Because of the large standard errors often found in determining them, and because some macrolides were not active in vivo above the highest practical dose (e.g. >150 mg/kg), we elected to use a coding system so that all 15 macrolides could be included in the analysis.…”

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confidence: 99%

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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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Section: T H Imentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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

et al. 1997

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“…Formic acid was sometimes preferred as the reducing agent [91]. These N-alkyl azetidines have been also obtained from the corresponding N-acyl compounds by carbonyl reduction after transformation into thioamides (Scheme 3.43) [88].…”

Section: 1312mentioning

confidence: 99%

Four‐Membered Heterocycles: Structure and Reactivity

Rousseau

Robin

2011

Modern Heterocyclic Chemistry

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Antibiotics, Macrolides

Kirst

2001

Kirk-Othmer Encyclopedia of Chemical Technology

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Macrolide antibiotics are well‐established antimicrobial agents in clinical and veterinary medicine. These agents can be administered orally and are generally used to treat infections in the respiratory tract, skin and soft tissues, and genital tract caused by gram‐positive organisms, Mycoplasma species, and certain susceptible gram‐negative and anaerobic bacteria. The macrolide class is large and structurally diverse. Macrolides are produced by fermentation of soil microorganisms. Additionally, structural modifications using both chemical and microbiological means have yielded biologically active semisynthetic derivatives. The term macrolide was introduced to denote the class of substances produced by Streptomyces species containing a macrocyclic lactone. Traditional macrolide antibiotics are divided into three families according to the size of the aglycone, which can be a 12‐, 14‐, or 16‐membered ring. Naturally occurring 14‐membered macrolides include erythromycin A and erythromycin B, as well as others. Erythromycin has been the principal subject of modification of 14‐membered macrolides; its semisynthetic derivatives include erythromycin ethyl succinate, roxithromycin, clarithromycin, azithromycin, dirithromycin, and others. More recently, the ketolide family has been discovered that exhibits activity against certain macrolide‐resistant strains, from which telithromycin and ABT‐773 are in clinical trials. The 16‐membered macrolides are divided into leucomycin‐ and tylosin‐related groups, which differ in the substitution pattern of their aglycones. Natural products include josamycin (leucomycin A 3 ), spiramycin, and others. The most prominent member of the second group is tylosin, an important veterinary antibiotic. Semisynthetic 16‐membered macrolides include miokamycin, rokitamycin, AIV‐tylosin, and tilmicosin. The advent of molecular biology has opened new possibilities for producing novel macrolides by genetic manipulations of biosynthetic pathways from macrolide‐producing microorganisms (combinatorial biosynthesis) that complement traditional chemical and microbiological approaches. Macrolides inhibit growth of gram‐positive bacteria, Mycoplasma species, and certain gram‐negative and anaerobic bacteria. Susceptible gram‐positive bacteria include many species of Staphylococcus and Streptococcus ; susceptible gram‐negative bacteria include Bordetella pertussis, Legionella pneumophila, Moraxella catarrhalis , Campylobacter sp., Chlamydia sp., and Helicobacter pylori . Some derivatives have shown promising activity against non‐tuberculous mycobacteria. Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes. Bacterial resistance to macrolides is often accompanied by cross‐resistance to lincosamide and streptogramin B antibiotics (MLS‐resistance). Bacterial resistance to antibiotics usually results from modification of a target site, enzymatic inactivation, or reduced uptake into or increased efflux from bacterial cells. The principal side effects of macrolides are gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. Macrolide antibiotics are used clinically to treat infections resulting from susceptible organisms in the upper and lower respiratory tract, skin and soft tissues, and genital tract. They are generally used orally, although they can be given intravenously. Macrolides are regarded as among the safest of antibiotics. A few macrolides are used in veterinary medicine, such as tylosin and tilmicosin which are used to control respiratory diseases and other infections in poultry, pigs, and cattle.

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Repromicin Derivatives with Potent Antibacterial Activity against Pasteurella multocida

Cited by 11 publications

References 7 publications

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

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

Four‐Membered Heterocycles: Structure and Reactivity

Antibiotics, Macrolides

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