Modification of Lincomycin

Magerlein, Barney J.

doi:10.1016/s0065-2164(08)70544-6

Cited by 41 publications

(37 citation statements)

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“…In vitro antimicrobial activity of clindamycin against group A s.treptococci is approximately the same as that of lincomycin on a weight basis (10,11,14). In mice infe\9eAiih group A streptococci, the oral mean 41twe dose is significantly lower for clindamycin than for lincomycin (9). In men, oral clindamycin is absorbed two or three times more efficiently than is oral lincomycin, but the average half-life of serum clindamycin activity (2.4 h) after a single usual 150-mg dose is less than the average half-life of serum lincomycin activity (5.2 h) after a single usual 500-mg dose (11,20).…”

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confidence: 94%

Streptococcal Pharyngitis Therapy: Comparison of Clindamycin Palmitate and Potassium Phenoxymethyl Penicillin

Stillerman

Isenberg

Facklam

1973

Antimicrob Agents Chemother

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Clindamycin palmitate and potassium phenoxymethyl penicillin were evaluated in 103 children with upper respiratory illnesses and pharyngeal group A streptococci, from November 1970 to July 1971. The children were assigned randomly by weight to one of the antibiotic regimens given orally for 10 days. Clindamycin palmitate and potassium phenoxymethyl penicillin dosages were 75 and 125 mg, respectively, in 5 ml tid for children weighing less than 25 kg, and 150 and 250 mg, respectively, in 10 ml bid for children weighing 25 kg or more. Recurrences of the original streptococcal group A, M, and T types within 3 weeks after the end of treatment were classified as failures. The failure rates were: clindamycin palmitate, 10% (5 of 52), and potassium phenoxymethyl penicillin, 18% (9 of 51). Possible drug-related rashes were observed in 8 of 52 clindamycin palmitate-treated patients. The geometric mean minimal inhibitory concentrations of clindamycin and penicillin against 103 isolates of group A streptococci were 0.033 and 0.007 ,g/ml, respectively. The serum concentrations about 70 min after ingesting 150 mg of clindamycin palmitate averaged 3.8 ,ug/ml and after 250 mg of potassium phenoxymethyl penicillin averaged 0.9 gg/ml. Clindamycin palmitate was as effective as potassium phenoxymethyl penicillin in eradicating group A streptococci from the pharynx in tid and bid regimens. Nevertheless, because of its rash-producing tendency in some patients and higher cost, clindamycin palmitate should not be preferred to penicillin for treatment of streptococcal sore throat in the non-penicillin-allergic patient.This investigation was initiated as a pilot study in evaluating the efficacy and side effects of two regimens of clindamycin palmitate and two of potassium phenoxymethyl penicillin (K penicillin V) against group A streptococci in upper respiratory illnesses.Clindamycin palmitate, a new semisynthetic derivative of lincomycin in the form of flavored granules, is a water-soluble ester of clindamycin [7 (S)-chloro-7-deoxylincomycin] and palmitic acid. The palmitate ester is rapidly hydrolyzed to the microbiologically active clindamycin base after ingestion of the granules in a pediatric suspension. The suspension of clindamycin palmitate was introduced in place of clindamycin hydrochloride, which is available in capsule form because of the objectionable taste of the hydrochloride. In vitro antimicrobial activity of clindamycin against group A

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confidence: 94%

Streptococcal Pharyngitis Therapy: Comparison of Clindamycin Palmitate and Potassium Phenoxymethyl Penicillin

Stillerman

Isenberg

Facklam

1973

Antimicrob Agents Chemother

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“…Various LIN derivatives have been prepared chemically, and in particular, the 4Ј-alkyl-4Ј-depropyllincomycin set has been determined to be more active and have a broader antimicrobial spectrum than LIN has. Of this set, 4Ј-butyl, pentyl, and hexyl analogs have been shown to be particularly effective (12,13). Moreover, demethylated and chlorinated 4Ј-alkyl-1Ј-demethyl-4Ј-depropylclindamycins had higher activities against Plasmodium spp.…”

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confidence: 99%

“…This phenomenon has been observed for various enzymes involved in the biosyntheses of secondary metabolites (8,19,21) and enables a great structural diversity of products. The antimicrobial activities of LIN and CLI derivatives with extended alkyl chains against a collection of Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Salmonella schottmuelleri strains have been determined previously (12). We used a set of 13 clinical macrolide-and/or lincosamideresistant Staphylococcus isolates (15-17) for a series of experiments evaluating the antimicrobial activity of BULIN and PELIN, depending on the presence of certain resistance genes.…”

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confidence: 99%

Mutasynthesis of Lincomycin Derivatives with Activity against Drug-Resistant Staphylococci

Ulanová

Novotná

Smutná

et al. 2010

Antimicrob Agents Chemother

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The lincomycin biosynthetic gene lmbX was deleted in Streptomyces lincolnensis ATCC 25466, and deletion of this gene led to abolition of lincomycin production. The results of complementation experiments proved the blockage in the biosynthesis of lincomycin precursor 4-propyl-L-proline. Feeding this mutant strain with precursor derivatives resulted in production of 4-butyl-4-depropyllincomycin and 4-pentyl-4-depropyllincomycin in high titers and without lincomycin contamination. Moreover, 4-pentyl-4-depropyllincomycin was found to be more active than lincomycin against clinical Staphylococcus isolates with genes determining low-level lincosamide resistance.Lincosamides form a small yet clinically important group of antibiotics. One of the naturally occurring members of this group, lincomycin A (LIN), is active against many Gram-positive bacteria, such as staphylococci and streptococci. Its semisynthetic derivative clindamycin (CLI) is prescribed for the treatment of some infections caused by anaerobic bacteria and is also applied against the causative agent of malaria, Plasmodium falciparum (9,22).Biosynthesis of lincomycin proceeds via two separate branches from tyrosine and D-glucose to the aglycone 4-propyl-L-proline (PPL) and methylthiolincosamide (MTL), respectively. Condensation of these two precursors via an amide bond by a multimeric synthetase yields N-demethyllincomycin (NDL), which is subsequently methylated to form LIN (3) (Fig. 1A). Various LIN derivatives have been prepared chemically, and in particular, the 4Ј-alkyl-4Ј-depropyllincomycin set has been determined to be more active and have a broader antimicrobial spectrum than LIN has. Of this set, 4Ј-butyl, pentyl, and hexyl analogs have been shown to be particularly effective (12, 13). Moreover, demethylated and chlorinated 4Ј-alkyl-1Ј-demethyl-4Ј-depropylclindamycins had higher activities against Plasmodium spp. than clindamycin did (14). These more potent 4Ј-alkyl derivatives of lincomycin can be prepared by a multistep and costly chemical synthesis (13). Alternatively, feeding or genetic modifications of the natural biosynthetic pathway could be used. For example, the addition of PPL derivatives with extended alkyl residues to fermentation broths of a producer strain in a process termed precursor-directed biosynthesis has been described previously (25). This resulted in a mixture of both LIN and its more biologically active derivative being produced, which is not desirable because of the need to separate and purify the product of interest.In this study we present a new mutasynthetic approach to the preparation of the two known 4Ј-alkyl-4Ј-depropyllincomycins (Fig. 1B) by feeding a mutant strain defective in PPL biosynthesis with PPL derivatives as a practical alternative to total chemical synthesis. We tested the biological activity of these LIN derivatives on a collection of Staphylococcus strains with defined resistance profiles that have been described previously (15)(16)(17).The early reactions involved in biosynthesis of proline derivatives...

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“…The present paper describes our results on the chemica modification of clindamycin (3). During our work c primary goal was to perform syntheses of the new antibiotic analogues which do not require temporary protection of the existing functions of the starting molecules.…”

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“…Solvents: Dist. water (1,3); 30% MeOH (5b); 50% MeOH (5a, 5c, 5d); DMSO-H2O (7:3) (5e). MHA: Mueller Hinton agar (Nissui) 37°C, 20 hours.…”

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Semisynthetic Modification of Antibiotic Lincomycin.

Sztaricskai

Dinya

et al. 1996

J. Antibiot.

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Modification of Lincomycin

Cited by 41 publications

References 38 publications

Streptococcal Pharyngitis Therapy: Comparison of Clindamycin Palmitate and Potassium Phenoxymethyl Penicillin

Streptococcal Pharyngitis Therapy: Comparison of Clindamycin Palmitate and Potassium Phenoxymethyl Penicillin

Mutasynthesis of Lincomycin Derivatives with Activity against Drug-Resistant Staphylococci

Semisynthetic Modification of Antibiotic Lincomycin.

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