Lincomycin Derivatives Research Articles

The Effect Of Streptomycin And Clindamycin On Dnase I Activity On The Quality Of Dna Of Salivary Origin

Deoxyribonucleic acid (DNA) contains genetic material with all an individual’s information. Saliva has the potential to be a good source of human DNA. When compared to blood sampling, saliva is easier to collect and the collection process is non-invasive. However, human DNA collected from saliva has the potential to be degraded due to deoxyribonuclease (DNase) activity in saliva. DNase activity can be inhibited by antibiotics, such as aminoglycoside antibiotics and lincomycin derivatives. This study aimed to determine the effect of streptomycin and clindamycin on DNAse I activity against the quality of human genomic DNA from saliva. The sampling technique was that samples were collected from 9 subjects with each subject flowing into a saliva pot. Before saliva collection, subjects were asked to rinse their mouth with a solution of chlorhexidine gargle (Listerin™) for 30 seconds, then the samples were divided into four groups. The average concentration of DNA extracted from the spin-column method was 32.91 g/mL (7.10-99.45 g/mL) while the average purity was 1.813 g/mL (1.639-2.043 g/mL). With clindamycin treatment, PCR was able to amplify the human NOTCH2 gene (~704 bp) while various concentrations of streptomycin produced multiple bands of ~100 bp. The concentration of 3.2 mM clindamycin effectively inhibits DNAse I activity and can amplify the human NOTCH2 gene while streptomycin cannot protect.

Discovery of Novel Lincomycin Derivatives Effective against Resistant Streptococcus pneumoniae and Streptococcus pyogenes Possessing ErmB Gene

Discovery of Novel Lincomycin Derivatives Effective against Resistant Streptococcus pneumoniae and Streptococcus pyogenes Possessing ErmB Gene

Antibiotic use in nasal bone fracture: a nationwide population-based cohort study in Korea.

BackgroundProphylactic antibiotics are commonly used in craniofacial surgeries. Despite the low risk of surgical site infection after nasal surgery, a lack of consensus regarding the use of antibiotic prophylaxis in the closed reduction of nasal bone fractures has led to inappropriate prescribing patterns. Through this study, we aimed to investigate the status of prophylactic antibiotic use in closed reductions of nasal bone fractures in Korea.MethodsThis retrospective cohort study was conducted using data from the National Health Insurance Service-National Sample Cohort of Korea from 2005 to 2015. We analyzed the medical records of patients who underwent closed reduction of nasal bone fractures. The sex, age, region of residence, comorbidities, and socioeconomic variables of the patients were collected from the database. Factors that affect the prescription of perioperative antibiotics were evaluated using multivariate logistic regression analysis.ResultsA total of 3,678 patients (mean± standard deviation of age, 28.7± 14.9 years; 2,850 men [77.5%]; 828 women [22.5%]) were included in this study. The rate of antibiotic prescription during the perioperative period was 51.4%. Approximately 68.8% of prescriptions were written for patients who had received general anesthesia. The odds of perioperative prophylactic antibiotic use were significantly higher in patients who received general anesthesia than who received local anesthesia (odds ratio, 1.59). No difference was found in terms of patient age and physician specialty. Second-generation cephalosporins were the most commonly prescribed antibiotic (45.3%), followed by third- and first-generation cephalosporins (20.3% and 18.8%, respectively). In contrast, lincomycin derivatives and aminoglycosides were not prescribed.ConclusionThe findings of this study showed that there was a wide variety of perioperative antibiotic prescription patterns used in nasal bone surgeries. Evidence-based guidance regarding the prescribing of antimicrobial agents for the closed reduction of nasal bone fractures should be considered in future research.

Characterization of compound A, a novel lincomycin derivative active against methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is one of causative bacteria for hospital- and community-acquired infections. In order to overcome MRSA infection, we synthesized compound A, a lincomycin derivative, and evaluated the biological properties. The MIC50 and MIC90 values of compound A against MRSA clinical isolates, which were susceptible to clindamycin, from infected skin in Japan were 0.12 and 0.25 μg ml-1, respectively, and those against hospital-acquired MRSA with clindamycin resistance were 1.0 and 2.0 μg ml-1, respectively. Linezolid non-susceptible MRSA selected in the laboratory had mutations in the 23S rRNA gene and exhibited cross-resistance to compound A. MRSA non-susceptible to compound A selected in laboratory was not cross-resistant to linezolid, implying that the binding site to 23S rRNA partly overlaps with clindamycin and linezolid. The in vivo efficacies of compound A against mouse skin abscess model infected with clindamycin-susceptible and -resistant MRSA were superior to those of clindamycin and linezolid, respectively. The well-known linezolid-induced myelosuppression is caused by its inhibitory effect on mitochondrial function, but inhibition was weaker for compound A than that of linezolid. In short, compound A has broader anti-MRSA activities than clindamycin and linezolid due to additional binding site, and demonstrated preferable safety profile as a potential anti-MRSA drug.

Synthesis and antibacterial activity of novel lincomycin derivatives. IV. Optimization of an N-6 substituent

The design and synthesis of lincomycin derivatives modified at the C-6 and C-7 positions are described. A substituent at the C-7 position is a 5-aryl-1,3,4-thiadiazol-2-yl-thio group that generates antibacterial activities against macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes carrying an erm gene. An additional modification at the C-6 position was explored in application of information regarding pirlimycin and other related compounds. These dual modifications were accomplished by using methyl α-thiolincosaminide as a starting material. As a result of these dual modifications, the antibacterial activities were improved compared with those of compounds with a single modification at the C-7 position. The antibacterial activities of selected compounds in this report against macrolide-resistant S. pneumoniae and S. pyogenes with an erm gene were superior to those of telithromycin.

Synthesis and SARs of novel lincomycin derivatives Part 5: optimization of lincomycin analogs exhibiting potent antibacterial activities by chemical modification at the 6- and 7-positions.

In order to modify lincomycin at the C-6 and C-7 positions, we prepared target molecules, which have substituted pipecolinic acid at the 6-amino group and a para-substituted phenylthio group at the C-7 position, in application of palladium-catalyzed cross-coupling as a key reaction. As the result of structure-activity relationship (SAR) studies at the 6-position, analogs possessing 4'-cis-(cyclopropylmethyl)piperidine showed significantly strong antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with an erm gene. On the basis of SAR, we further synthesized novel analogs possessing 4'-cis-(cyclopropylmethyl)piperidine by transformation of a C-7 substituent. Consequently, novel derivatives possessing a para-heteroaromatic-phenylthio group at the C-7 position exhibited significantly strong activities against S. pneumoniae and S. pyogenes with an erm gene even when compared with those of telithromycin. Finally, in vivo efficacy of selected two derivatives was evaluated in a rat pulmonary infection model with resistant S. pneumoniae with erm + mef genes. One of them exhibited strong and constant in vivo efficacy in this model, and both compounds showed strong in vivo efficacy against resistant S. pneumoniae with a mef gene.

Synthesis and antibacterial activity of novel lincomycin derivatives. III. Optimization of a phenyl thiadiazole moiety.

Lincomycin derivatives that have a 5-(2-nitrophenyl)-1,3,4-thiadiazol-2-yl thio moiety at the 7-position were synthesized. 5-Substituted 2-nitrophenyl derivatives showed potent antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene. Antibacterial activities of the 4,5-di-substituted 2-nitrophenyl derivatives were generally comparable to those of telithromycin (TEL) against S. pneumoniae with erm gene and clearly superior to those of TEL against S. pyogenes with erm gene. Compounds 6 and 10c that have a methoxy group at the 5-position of the benzene ring exhibited activities comparable to TEL against Haemophilus influenzae. These results suggest that lincomycin derivatives modified at the 7-position would be promising compounds as a clinical candidate. We would like to dedicate this article to the special issue for late Professor Dr. Hamao Umezawa in The Journal of Antibiotics.The Journal of Antibiotics advance online publication, 5 July 2017; doi:10.1038/ja.2017.59.

Synthesis and structure–activity relationships of novel lincomycin derivatives. Part 4: synthesis of novel lincomycin analogs modified at the 6- and 7-positions and their potent antibacterial activities

To modify lincomycin (LCM) at the C-6 and the C-7 positions, we firstly prepared various substituted proline intermediates (7, 11-15 and 17). These proline intermediates were coupled with methyl 1-thio-α-lincosamide and tetrakis-O-trimethylsilylation followed by selective deprotection of the TMS group at the 7-position gave a wide variety of key intermediates (23-27, 47 and 50). Then, we synthesized a variety of novel LCM analogs modified at the 7-position in application of the Mitsunobu reaction, an SN2 reaction, and a Pd-catalyzed cross-coupling reaction. Compounds 34 and 35 (1'-NH derivatives) exhibited enhanced antibacterial activities against resistant pathogens with erm gene compared with the corresponding 1'-N-methyl derivatives (3 and 37). On the basis of reported SAR, we modified the 4'-position of LCM derivatives possessing a 5-(2-nitrophenyl)-1,3,4-thiadiazol-2-yl group at the C-7 position. Compound 56 showed significantly potent antibacterial activities against S. pneumoniae and S. pyogenes with erm gene, and its activities against S. pneumoniae with erm gene were improved compared with those of 34 and 57. Although we synthesized novel analogs by transformation of a C-7 substituent focusing on the 1'-demethyl framework to prepare very potent analogs 73 and 75, it was impossible to generate novel derivatives exhibiting stronger antibacterial activities against S. pneumoniae with erm gene compared with 56.

Synthesis and antibacterial activity of novel lincomycin derivatives. I. Enhancement of antibacterial activities by introduction of substituted azetidines.

The synthesis and antibacterial activity of (7S)-7-sulfur-azetidin-3-yl lincomycin derivatives are described. Modification was achieved by a simple reaction of (7R)-7-O-methanesulfonyllincomycin and the corresponding substituted azetidine-2-thiol. Several compounds first showed moderate antibacterial activity against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene as lincomycin derivatives.

Synthesis and structure-activity relationships of novel lincomycin derivatives. Part 1. Newly generated antibacterial activities against Gram-positive bacteria with erm gene by C-7 modification.

We synthesized 7(S)-7-deoxy-7-arylthiolincomycin derivatives possessing a heterocyclic ring at the C-7 position via sulfur atom by either Mitsunobu reaction of 2,3,4-tris-O-(trimethylsiliyl)lincomycin or SN2 reaction of 7-O-methanesulfonyl-2,3,4-tri-O-trimethylsiliyllincomycin. As a result, 7(S)-7-deoxy-7-arylthiolincomycin derivatives 16, 21 and 27 exhibited antibacterial activities against respiratory infection-related Gram-positive bacteria with erm gene, although clindamycin did not have any activities against those pathogens. Furthermore, 7(S)-configuration of lincomycin derivatives was found to be necessary for enhancing antibacterial activities from the comparison results of configurations of 16 (S-configuration) and 30 (R-configuration) at the 7-position.

Triclosan and prescription antibiotic exposures and enterolactone production in adults

BackgroundThe gut microbiome plays an important role in the development of disease. The composition of the microbiome is influenced by factors such as mode of delivery at birth, diet and antibiotic use, yet the influence of environmental chemical exposures is largely unknown. The antimicrobial compound triclosan, found in many personal care products and widely detected in human urine, is an environmental exposure for which systemic microbiotic effects may be of particular interest. To investigate the relationship between triclosan and gut microflora, we assessed the association between triclosan and enterolactone, an intestinal metabolite that is produced via bacterial transformation of dietary lignans (seeds, nuts) and has known susceptibility to oral antibiotics. MethodsWe examined urinary triclosan and enterolactone for 2005-2008 U.S. National Health and Nutrition Examination Survey subjects, aged ≥20 years (n=3041). We also examined the association between prescription antibiotic use and enterolactone to confirm its susceptibility to changes in bacterial composition of the body. Associations between natural log-transformed enterolactone and (1) detected vs. not detected (<2.3ng/mL) triclosan, (2) triclosan quintiles (Q1–Q5), and (3) any vs. no antibiotics were estimated with multiple linear regression, adjusting for sex, age, race, body mass index, poverty income ratio, education, fiber intake, bowel movement frequency, cotinine and creatinine (n=2441). ResultsTriclosan was detected in 80% of subjects (range: <2.3–3620ng/mL), while enterolactone was detected in >99% of subjects (range: <0.1–122,000ng/mL). After adjustment, enterolactone was not associated with triclosan (detect vs. non-detect: β= 0.07 (95% CI: −0.15, 0.30); Q5 (≥104.5ng/mL) vs. Q1 (none): β= 0.06 (95% CI: −0.21, 0.34)). In sex-stratified analyses, triclosan was associated with higher enterolactone in women (detect vs. non-detect: β= 0.31 (95% CI: −0.07, 0.70), but not men β= −0.18 (95% CI: −0.47, 0.11). However, any antibiotic use (n=112), as compared to no antibiotic use, was associated with significantly lower enterolactone (β=−0.78 (95%CI: −1.22, −0.36)), with no sex-specific effects. This association was driven by inverse associations with the following antibiotic classes: macrolide derivatives, quinolones, sulfonamides, and lincomycin derivatives. ConclusionsAntibiotics, but not triclosan, are negatively associated with urinary enterolactone. Antibiotics may reduce enterolactone by killing certain gut bacteria. At levels detected in the U.S., triclosan does not appear to be acting similarly, despite broad antimicrobial properties. Additional study of determinants of triclosan exposure and enterolactone production may be needed to better understand positive associations among women.

Synthesis of novel lincomycin derivatives and their in vitro antibacterial activities

Synthesis of novel lincomycin derivatives and their in vitro antibacterial activities

Mutasynthesis of Lincomycin Derivatives with Activity against Drug-Resistant Staphylococci

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.

Clindamycin vasculitis in patients with peripheral arterial vascular disease

Clindamycin was first synthesized in 1966. It is a chemical derivative of lincomycin with activity against aerobic gram-positive and gram-negative bacteria. The side effects include diarrhea, pseudomembranous colitis, metallic taste in the mouth, transient elevation of transaminases, granulocytopenia, thrombocytopenia, and rash. The incidence of maculopapular rashes has been reported to be approximately 10%. Leukocytoclastic angitis or vasculitis induced by clindamycin has been reported (Lambert et al., Cutis 30:615–619, 1982) and this is a very serious complication in patients with peripheral arterial vascular diseases which may leads to severe and deep necrotizing vasculitis. We report two cases of necrotizing vasculitis due to clindamycin which was used for the treatment of chronic wounds in patients suffering of peripheral vascular disease.

Synthesis and Evaluation of S‐ and C(1)‐Substituted Analogues of Lincomycin

Abstractmagnified imageNew thioglycosides and C(1)‐alkylated thioglycosides (S‐ulosides) of lincomycin were synthesized, and their antibiotic activities were determined. The S‐aryl and S‐arylalkyl analogues 11a–11i were obtained by S‐glycosylation of the sulfoxides 7 with arenethiols, or by S‐alkylation of the thiol 14 with alkyl bromides. Lincomycin derivatives 27, 32a, 32b, 38a, 38b, 44, and 47 were prepared via Henry reaction or Michael addition of the lincosamine‐derived 1‐deoxy‐1‐nitropyranoses 22. The S‐alkyl derivatives showed a similar activity and specificity as lincomycin. Lipophilic S‐uloside analogues were two‐ to fourfold less active than the parent antibiotic, whilst the hydrophilic analogues were inactive.

Lincomycin, cultivation of producing strains and biosynthesis.

Lincomycin and its derivatives are antibiotics exhibiting biological activity against Gram-positive bacteria. The semi-synthetic chlorinated lincomycin derivative is used in clinical practice. The chemical structure of lincosamide antibiotics, cultivation of producing strains and analytical procedures used for separation and isolation of these compounds are described in this review. Biosynthesis of lincomycin and related compounds and its genetic control are briefly discussed.

Clindamycin

Clindamycin (CM) is a chemically synthesized derivative of lincomycin, which originally was isolated from the soil actinomycete Streptomyces lincolnesis in 1962. CM essentially has replaced lincomycin therapeutically because of its broader antimicrobial spectrum and enhanced gastrointestinal absorption. CM inhibits bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome, thereby blocking peptide chain initiation and elongation. CM functions as a bacteriostatic agent; however, in certain clinical situations, it can be considered bactericidal. Interestingly, the ribosomal binding sites of macrolide antibiotics (erythromycin, clarithromycin, etc) and chloramphenicol appear to overlap, leading to the theoretic concern of drug antagonism should these medications be used in combination.

Enhancement of the curative activity of primaquine by concomitant administration of mirincamycin.

Mirincamycin, a lincomycin derivative with unequivocal but limited activity against the pre-erythrocytic and persisting exoerythrocytic stages of Plasmodium cynomolgi, has been evaluated for capacity to enhance the radical curative potential of the conventional primaquine-chloroquine combination. Established infections with sporozoites of the above plasmodium in rhesus monkeys served this evaluation. The results showed that the dose of primaquine required for cure of 50% of active infections was reduced by one-half to two-thirds by coadministration with 2.5 mg of mirincamycin per kg, 1/16 the 50% curative dose of this lincomycin derivative when used in a mono-drug regimen. The dimensions of the enhancement of the curative activity of primaquine were inversely related to the size of the sporozoite inoculum. The smallest dose of mirincamycin productive of enhancement was 2.5 mg/kg; whether doses larger than 2.5 mg/kg would have been more effective was not determined. There is much to be done before it is known whether a mirincamycin-primaquine combination is useful for suppressive cure or radical cure of the human malarias. Irrespective of that result, the current study serves to focus attention on a somewhat novel approach to the development of more effective and better-tolerated regimens for radical cure, an alternative to the empirical chemical synthesis and screening approach that has dominated searches heretofore.

Clindamycin: a review of fifteen years of experience.

Clindamycin, the 7(S)-chloro-7-deoxy derivative of lincomycin, has stood the test of time in the treatment of anaerobic infections. Clindamycin inhibits protein synthesis by acting on the 50S ribosomal subunits of bacteria. The colitis resulting from the use of clindamycin has been extensively studied and is now easily manageable. Although newer antibiotics active against anaerobes are available, clindamycin remains a reliable and well-tested antibiotic for use in anaerobic infections.

A reappearance of antibiotic-induced pseudomembranous enterocolitis.

Four proved cases of pseudomembranous enterocolitis are presented. In each case either lincomycin or clindamycin (a derivative of lincomycin) was given. Use of such broad spectrum antibiotics appears to be related to the increased incidence of pseudomembranous enterocolitis. Roentgen findings include thickening of the mucosal folds of the small intestine and pseudomembrane formation. When the colon is involved, it may also show thickening and dilatation. With use of contrast medium, expected radiographic findings are edema, shaggy appearance of the mucosa and/or ulceration, findings similar to those seen in inflammatory colitis.