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Objectives: Solithromycin is a fluoroketolide that is considered to be a noninducing antibiotic for macrolide–lincosamide–streptogramin B resistance mediated by erm genes. The exact activity of solithromycin to induce erm gene expression remains to be determined. Materials and Methods: The potential of solithromycin to induce erm(A), erm(C), and erm(B) gene expression was examined using a lacZ reporter assay, double-disk diffusion test, and determination of the minimal inhibitory concentration after incubation with subinhibitory concentration of different antibiotics. Results: Neither solithromycin nor the ketolides telithromycin and cethromycin induced erm(A) or erm(C) gene expression. However, solithromycin could significantly induce erm(B) gene expression at levels greater than that seen for cethromycin and clindamycin, but less than that for erythromycin, rokitamycin, and telithromycin. Conclusion: Solithromycin does not induce erm(A) and erm(C) gene expression, but does induce erm(B) gene expression, although to a weaker extent than that seen for macrolides. [ABSTRACT FROM AUTHOR]

A series of novel C11 substituted 14-membered 2-fluoro ketolides were synthesized and evaluated for their antibacterial activity against erythromycin-resistant and erythromycin-susceptible clinical isolates and strains from ATCC. The overall antibacterial spectra of the semi-synthetic antibiotics are similar to that of telithromycin (TEL) and most of them exhibited excellent activity against Gram-positive bacteria (S. epidermidis , S. pneumoniae , S. aureus) and several Gram-negative bacteria (M. catarrhalis , H. influenza). Compounds 11c , 11g , 11h , 11q , 12a , 12b , 12d and 12e displayed 4–16 fold more potency than TEL against all the tested erythromycin-resistant S. epidermidis strains and S. pneumonia SPN19-8 and SPN19-8. Compounds 11b , 11c , 11e , 11g , 11h , 11q , 12a , 12b and 12c showed at least 8 fold potency than TEL against erythromycin-resistant M. catarrhalis BCA19-5 and BCA19-6. Molecular docking suggested compound 12d oriented the macrolide ring and side chain similarly to solithromycin (SOL). Noticeably an additional hydrogen bond was observed between the Lys90 residue of ribosome protein L22 and the carbamate group at the C11 position, which might provide a rational explanation for the enhanced antibacterial activity of target compounds. Therefore this research would offer a new perspective for further structural optimization of the C11 side chain. Based on the results of antibacterial activity, cytotoxicity and structural diversity, 5 compounds (11a , 11b , 11h , 12d and 12i) were selected for the stability testing of human liver microsomes and compound 11a exhibited preferable metabolic stability. [Display omitted] • Novel 14-membered 2-fluro ketolides are featured with the carbamate group. • The configuration of 2, 10-position was analysized and determinated. • The SAR on the C-11 position was described. • Ketolides exhibited improved potencies against some resistant bacteria. • Molecular docking suggested an additional hydrogen bond on the carbamate group. [ABSTRACT FROM AUTHOR]

Macrolide antibiotics inhibit protein synthesis by targeting the bacterial ribosome. They bind at the nascent peptide exit tunnel and partially occlude it. Thus, macrolides have been viewed as ‘tunnel plugs’ that stop the synthesis of every protein. More recent evidence, however, demonstrates that macrolides selectively inhibit the translation of a subset of cellular proteins, and that their action crucially depends on the nascent protein sequence and on the antibiotic structure. Therefore, macrolides emerge as modulators of translation rather than as global inhibitors of protein synthesis. The context-specific action of macrolides is the basis for regulating the expression of resistance genes. Understanding the details of the mechanism of macrolide action may inform rational design of new drugs and unveil important principles of translation regulation. [ABSTRACT FROM AUTHOR]

Efficient approaches for the utilization of waste sewage sludge have been widely studied. One of them is to use it for the bioenergy production, specifically methane gas which is well-known to be driven by complex bacterial interactions during the anaerobic digestion process. Therefore, it is important to understand not only microorganisms for producing methane but also those for controlling or regulating the process. In this study, azithromycin analogs belonging to macrolide, ketolide, and lincosamide groups were applied to investigate the mechanisms and dynamics of bacterial community in waste sewage sludge for methane production. The stages of anaerobic digestion process were evaluated by measuring the production of intermediate substrates, such as protease activity, organic acids, the quantification of bacteria and archaea, and its community dynamics. All azithromycin analogs used in this study achieved a high methane production compared to the control sample without any antibiotic due to the efficient hydrolysis process and the presence of important fermentative bacteria and archaea responsible in the methanogenesis stage. The key microorganisms contributing to the methane production may be Clostridia, Cladilinea, Planctomycetes, and Alphaproteobacteria as an accelerator whereas Nitrosomonadaceae and Nitrospiraceae may be suppressors for methane production. In conclusion, the utilization of antibiotic analogs of macrolide, ketolide, and lincosamide groups has a promising ability in finding the essential microorganisms and improving the methane production using waste sewage sludge. [ABSTRACT FROM AUTHOR]

Purpose. The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, clinical safety, and current regulatory status of solithromycin are reviewed. Summary. Solithromycin is a novel ketolide antibiotic developed for the treatment of community-acquired bacterial pneumonia (CABP). Its pharmacologic, pharmacokinetic, and pharmacodynamic properties provide activity against a broad range of intracellular organisms, including retained activity against pathogens displaying various mechanisms of macrolide resistance. Phase III clinical trials of solithromycin demonstrated noninferiority of both oral and i.v.-to-oral regimens of 5-7 days' duration compared with moxifloxacin for patients with moderately severe CABP. -Nearly one third of patients receiving i.v. solithromycin experienced infusion-site reactions. Although no liver-related adverse events were reported in patients receiving oral solithromycin, more patients receiving i.v.-to-oral solithromycin experienced asymptomatic, transient transaminitis, with alanine transaminase levels of >3 to >5 times the upper limit, compared with those treated with moxifloxacin. These results led the Food and Drug Administration to conclude that the solithromycin new drug application was not approvable as filed, adding that the risk of hepatotoxicity had not yet been adequately characterized. The agency further recommended a comparative study of patients with CABP to include approximately 9,000 patients exposed to solithromycin in order to exclude drug-induced liver injury events occurring at a rate of 1 in 3,000 with 95% probability. Conclusion. Solithromycin is a novel ketolide antibiotic with activity against a broad spectrum of intracellular organisms, including those displaying macrolide resistance. While demonstrating noninferiority to a current first-line agent in the treatment of CABP, concerns for drug-induced liver injury and infusion-site reactions have placed its regulatory future in doubt. [ABSTRACT FROM AUTHOR]

Erythromycin was long viewed as a bacteriostatic agent. The erythromycin derivatives, 9-oxime ketolides have a species-specific bactericidal profile. Among them, the 3′-allyl version of the 9-oxime ketolide 1 (Ar = 3-quinolyl; 17a ) is bactericidal against Streptococcus pneumoniae and Streptococcus pyogenes. In contrast, the 2-fluoro analogs of 1 , 13a (Ar = 6-quinolyl), 13b (Ar = 3-quinolyl) and 24a (Ar = 4-isoquinolyl), show bactericidal activities against S. pneumoniae , Staphylococcus aureus and Moraxella catarrhalis , while the 2-fluoro analogs 13c (Ar = 3-aminopyridyl) and 24b (Ar = 3-carbamoylpyridyl) are only bactericidal against S. pneumoniae and Haemophilus influenzae . Reduction of the ketolides led to novel epiacylides, the 3- O -epimers of the acylides. Alteration of linker length ( 30b vs. 30a ), 2-fluorination ( 33 vs. 30a ) and incorporation of additional spacers at the 9-oxime or 6-OH ( 35 , 40 vs. 30a ) did not restore the epiacylides back to be as active as the acylide 31 . Molecular docking suggested that epimerization at the 3-position reshapes the orientation of the 3- O -sidechain and leads to considerably weaker binding with bacterial ribosomes. [ABSTRACT FROM AUTHOR]

Two strains of Streptococcus pneumoniae, one expressing the methyltransferase Erm(B) and the other negative for erm (B), were selected for solithromycin resistance in vitro either with direct drug selection or with chemical mutagenesis followed by drug selection. We obtained a series of mutants that we characterized by next-generation sequencing. We found mutations in various ribosomal proteins (L3, L4, L22, L32, and S4) and in the 23S rRNA. We also found mutations in subunits of the phosphate transporter, in the DEAD box helicase CshB, and in the erm (B)L leader peptide. All mutations were shown to decrease solithromycin susceptibility when transformed into sensitive isolates. Some of the genes derived from our in vitro screens were found to be mutated also in clinical isolates with decreased susceptibility to solithromycin. While many mutations were in coding sequences, some were found in regulatory regions. These included novel phenotypic mutations in the intergenic regions of the macrolide resistance locus mef (E)/ mel and in the vicinity of the ribosome binding site of erm (B). Our screens highlighted that macrolide-resistant S. pneumoniae can easily acquire resistance to solithromycin, and they revealed many new phenotypic mutations., Competing Interests: The authors declare no conflict of interest.

The fluoroketolide solithromycin is 2-fold more potent in vitro than telithromycin against pneumococci (including macrolide-resistant strains) and Haemophilus influenzae and very active on pathogens causing atypical pneumonia. In contrast, it is a 30-fold less potent inhibitor of nicotinic receptors incriminated in telithromycin toxicity. In Phase II/III trials, oral solithromycin once-daily (800 mg on day 1; 400 mg on days 2-5) proved effective and safe when compared to respiratory fluoroquinolones for the treatment of community-acquired bacterial pneumonia (CABP). A Phase III intravenous trial vs. moxifloxacin has been recently completed for the same indication. Solithromycin may restore interest in ketolides as a first-line therapy for CAPB. Solithromycin safety should nevertheless be confirmed in larger populations allowing for detection of rare adverse events. [ABSTRACT FROM AUTHOR]

The global emergence of antibacterial resistance among common and atypical respiratory pathogens in the last decade necessitates the strategic application of antibacterial agents. The use of bactericidal rather than bacteriostatic agents as first-line therapy is recommended because the eradication of microorganisms serves to curtail, although not avoid, the development of bacterial resistance. Bactericidal activity is achieved with specific classes of antimicrobial agents as well as by combination therapy. Newer classes of antibacterial agents, such as the fluoroquinolones and certain members of the macrolide/lincosamine/streptogramin class have increased bactericidal activity compared with traditional agents. More recently, the ketolides (novel, semisynthetic, erythromycin-A derivatives) have demonstrated potent bactericidal activity against key respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia pneumoniae, and Moraxella catarrhalis. Moreover, the ketolides are associated with a low potential for inducing resistance, making them promising first-line agents for respiratory tract infections.

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9-Oxime acylides have different SAR and binding modes from 9-oxime ketolides. An aminopyridyl or carbamoylpyridyl group anchored at the end of the 9-oxime 2-propargyl group is beneficial for antimicrobial activity. Both the 2-pyridyl and 3-pyridyl groups derived from 3-OH have stacking interactions with the base pair G2505/C2610 ( Escherichia coli numbering) of the bacterial rRNA. Compounds 3 presented characteristic features that belong to bactericidal agents when used against constitutive- erm resistant Staphylococcus aureus , susceptible and mef -encoded Streptococcus pneumoniae , inducible- erm resistant Streptococcus pyogenes , and Moraxella catarrhalis . A docking model indicated that the carbamoylpyridyl group of 3h may hydrogen bond to G2061 in addition to π–π stacking over the adenine of A2062 that proved to gate the tunnel for the egress of the nascent peptide. This study suggests that the 9-oxime acylides possess a bactericidal mechanism that is different from the traditional near-complete inhibition of protein synthesis. These studies provide a foundation for the rational design of macrolide antibiotics. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of 10-hydroxyl ketolide derivatives were synthesized, during which a distinctive intermediate, 3-O-descladinosyl-3-oxo-11-deoxy-10,11-epoxy-6-O-methylerythromycin A, was obtained from 6-O-methylerythromycin A. The structure and stereochemistry of this novel structure were confirmed via NMR and X-ray crystallography. Moreover, antibacterial evaluations were established in order to assess our modifications and acquire a deep understanding of the ketolides’ structure–activity relationship (SAR). [Copyright &y& Elsevier]

Abstract: A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b–8d, and 8h–8l displayed dramatically improved potency against inducibly MLSB-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Arolyl) possessed an MIC of 0.064 μg/mL against constitutively MLSB-resistant Streptococcus pneumoniae, and MICs of 0.032–0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9. [Copyright &y& Elsevier]

Abstract: A series of novel modified 5-O-desosamine-ketolides were synthesized. The 5-O-desosamine fragment was removed from ketolide by an efficient and mild manipulation. 4-O-substituted desosamine was introduced into the ketolide aglycon and various coupling methods were essayed for the glycosylation. Three novel ketolides were tested for in vitro antibacterial activity against a panel of susceptible and resistant pathogens. Compound 26 showed potent activity against all the methicillin-sensitivity and resistant pathogens. [Copyright &y& Elsevier]

Abstract: A novel series of ketolides with 11,12-sulfur contained aryl alkyl side chains were synthesized and evaluated for their antibacterial activity. These ketolides exhibited potent activity against key macrolide sensitive and resistant respiratory pathogens. The newly synthesized 9a, 9e, 9k and 9n showed a similar antimicrobial spectrum and comparable activity to telithromycin, the commercial ketolide antibacterial. [Copyright &y& Elsevier]

Abstract: A series of C-12 pyrazolinyl spiro ketolide derivatives were designed and synthesized. The C-12 modifications involved replacing the natural C-12 methyl group in clarithromycin core with different pyrazolinyl spiros via chemical synthesis. Potential anti-bacterial activities against both erythromycin-susceptible and erythromycin-resistant bacteria were reported. [ABSTRACT FROM AUTHOR]

Abstract: A facile and efficient route was presented to achieve 3-keto-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 8, 2,3-dehydro-3-O-allyl-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 11, and 3-O-allyl-clarithromycin 9-O-(3-aryl-E-2-propenyl) oxime derivatives 12. Among them, compound 8, particularly 8d (Ar = 6-quinolyl), exhibited improved antibacterial activities against erythromycin-susceptible Staphylococcus aureus and Streptococcus pneumoniae, and greatly enhanced activities against the resistant strains encoded by erm and mef genes, as compared to clarithromycin and azithromycin. [ABSTRACT FROM AUTHOR]

Abstract: CEM-101 is a novel fluorinated macrolide–ketolide with potent activity against bacterial pathogens that are susceptible or resistant to other macrolide–lincosamide–streptogramin B (MLSB)–ketolide agents. CEM-101 is being developed for oral and parenteral use in moderate to moderately severe community-acquired bacterial pneumonia. The objective of this study was to assess the activity of CEM-101 and comparators against contemporary respiratory tract infection (RTI) isolates. A worldwide sample of organisms was used, including Streptococcus pneumoniae [n =168; 59.3% erythromycin-resistant and 18 multidrug-resistant (MDR) serogroup 19A strains], Moraxella catarrhalis (n =21; 11 β-lactamase positive), Haemophilus influenzae (n =100; 48 β-lactamase positive), Haemophilus parainfluenzae and Haemophilus haemolyticus (n =12), and Legionella pneumophila (n =30). Testing and interpretation were performed using reference Clinical and Laboratory Standards Institute methods. CEM-101 was very potent against S. pneumoniae [minimum inhibitory concentration for 90% of the organisms (MIC90)=0.25mg/L; highest MIC at 0.5mg/L] and was 2- and ≥32-fold more active than telithromycin and clindamycin, respectively. CEM-101 also demonstrated potent activity against S. pneumoniae MDR-19A strains (MIC90=0.5mg/L). CEM-101 was the most potent antimicrobial agent tested against L. pneumophila, with all MIC values at ≤0.015mg/L (telithromycin MIC90=0.03mg/L). CEM-101 was as potent as azithromycin against Haemophilus spp. RTI pathogens (MIC90=2mg/L), with no variations for β-lactamase production. CEM-101 MIC values against M. catarrhalis were all at ≤0.5mg/L. Interestingly, CEM-101 potency was ca. 6log2 dilutions greater than telithromycin MIC results among 44 β-haemolytic streptococci having telithromycin MICs ≥2mg/L. CEM-101 exhibited the greatest potency and widest spectrum of activity against RTI pathogens among the tested MLSB–ketolide agents (azithromycin, clarithromycin, erythromycin, telithromycin, clindamycin and quinupristin/dalfopristin) and was comparable overall with levofloxacin. [Copyright &y& Elsevier]

Community-acquired pneumonia remains the primary infectious cause of death in the United States. At current levels of antimicrobial resistance, conventional agents are at risk of becoming less effective, and the need for new agents is pressing. Cethromycin is a new ketolide antibiotic being investigated for use in respiratory tract infections. To review its pharmacology, in vitro susceptibilities, pharmacokinetics, efficacy, safety, and drug interactions, we conducted a MEDLINE search restricted to English-language articles citing cethromycin or ABT-773 (its original designation) from 1990-May 2009. Additional data sources were identified from the references of selected articles. All published trials and available poster data citing cethromycin were selected for review. In vitro, cethromycin displays more potent antibacterial effects than its predecessor telithromycin. Cethromycin exhibits potent inhibition of both gram-positive and gram-negative respiratory pathogens. A new drug application for cethromycin was submitted to the United States Food and Drug Administration in 2008 for the treatment of community-acquired pneumonia. Clinical trial data in the treatment of respiratory tract infections support cethromycin's efficacy. The limited safety data have not included any reports of hepatotoxicity. If cethromycin proves to be safe with regard to hepatotoxicity, it has great promise as an alternative to current standard therapy for community-acquired respiratory infections, especially pneumonia. Given current resistance levels, cethromycin could provide more reliable coverage against common respiratory pathogens than traditional agents in the β-lactam and macrolide classes. [ABSTRACT FROM AUTHOR]

Abstract: In an effort to find new antibiotics, a novel series of 14-membered macrolides with imidazo[4,5-b]pyridinyl sulfur contained alkyl side chains has been synthesized based on commercially available clarithromycin. Chemical transformation of hydroxy group at position C-3 afforded range of ketolides and acylides. Compared to telithromycin, compound 15a demonstrated improved in vitro activity against erythromycin-susceptible and -resistant strains. [Copyright &y& Elsevier]

Abstract: Based on clinicians’ expectations of high concentrations of telithromycin (TEL) in tissues, combined with its excellent in vitro antimicrobial characteristics, TEL is casually considered as a potential therapeutic option for the therapy of minor cases of soft tissue or bite-wound infections. To clarify this clinically important issue, the present investigation was carried out to measure the pharmacokinetic profile of TEL in the interstitial space fluid (ISF) of skeletal muscle and subcutaneous adipose tissue by means of the microdialysis technique in 10 healthy subjects following repetitive daily doses of 800mg TEL. These data were compared with free concentrations of TEL determined in plasma. External controls for the present examination were the use of historic, single-dose data collected by our study group utilising identical methods and the same trial subjects. Despite an increase in the median half-life from ca. 3h after a single dose to ca. 10h at steady-state conditions in all compartments, accumulation of TEL in ISF of soft tissues and plasma was clinically non-relevant. Median free peak concentrations in plasma, skeletal muscle and subcutis were 0.52, 0.13 and 0.19mg/L, respectively. The median ratios of the tissue to plasma free areas under the concentration–time curves from 0 to 24h (fAUC0–24 tissue/fAUC0–24 plasma) were 0.27 and 0.58 for muscle and subcutis, respectively (P >0.05). The present multiple-dose investigation of TEL is in line with a previous single-dose study confirming that TEL 800mg/day may not be optimally effective in the therapy of soft tissue infections. [Copyright &y& Elsevier]

This Minireview summarizes the changes in the field of bacterial resistance to macrolide, lincosamide, streptogramin, ketolide, and oxazolidinone (MLSKO) antibiotics since the nomenclature review in 1999. A total of 66 genes conferring resistance to this group of antibiotics has now been identified and includes 13 new rRNA methylase genes, four ATP-binding transporter genes coding for efflux proteins, and five new inactivating enzymes. During this same time period, 73 new genera carrying known rRNA methylase genes and 87 new genera carrying known efflux and/or inactivating genes have been recognized. The number of bacteria with mutations in the genes for 23S rRNA, L4 and L22 ribosomal proteins, resulting in reduced susceptibility to some members of the group of MLSKO antibiotics has also increased and now includes nine different Gram-positive and 10 different Gram-negative genera. New conjugative transposons carrying different MLSKO genes along with an increased number of antibiotics and/or heavy metal resistance genes have been identified. These mobile elements may play a role in the continued spread of the MLSKO resistance genes into new species, genera, and ecosystems. [ABSTRACT FROM AUTHOR]

Abstract: Novel macrolide antibiotics which contain a methylene unit between two nitrogen atoms of carbamate groups or between two nitrogen atoms of one carbamate and one urea group were synthesized using the Curtius rearrangement. Such linkers were shown to be stable under physiological conditions, and the resulting ketolides show potent in vitro and in vivo activity against macrolide-resistant respiratory pathogens. The SAR of various heterocycles and linkers was established. [Copyright &y& Elsevier]

Abstract: C11, C12-cyclic urea analogues of ketolides were designed and synthesized by use of a novel ketene acetal intermediate. This intermediate enabled introduction of an amino group at C12 stereospecifically and in high yield. The resulting cyclic urea ketolides appear to have in vitro activity similar to that of telithromycin which contains a C11, C12 cyclic carbamate moiety. Some of the C2 fluorinated compounds have improved potency against erm-containing Streptococcus pyogenes. [Copyright &y& Elsevier]

Summary: Objectives: To determine global antibacterial resistance rates among community-acquired isolates of Streptococcus pneumoniae. Methods: Between 2001 and 2004, 20,142 S. pneumoniae isolates from 151 centres in 40 countries were collected and tested for susceptibility to common antibacterials in the PROTEKT surveillance study. Results: The prevalence of β-lactam and macrolide resistance did not change, but there was marked geographic variability. The most common macrolide resistance mechanism was ribosomal methylation mediated by erm(B), except in Canada, Greece and the USA where drug efflux mediated by mef(A) was predominant. The erythromycin minimum inhibitory concentration for mef(A) isolates increased significantly (P <0.001; χ 2 test). The global prevalence of macrolide-resistant isolates positive for both erm(B) and mef(A) was 12.0% in 2003–2004; erm(B)+mef(A) strains were particularly common in South Korea (40.8%), South Africa (46.4%) and the USA (29.6%). Telithromycin was the most active antibacterial tested. Over the studied period, ≥99.7% of all isolates and >99% of erythromycin-resistant isolates, irrespective of genotype, were susceptible to telithromycin. Conclusions: These results confirm the high worldwide prevalence of resistance to commonly used antibacterial agents and multiple resistance phenotypes among clinical isolates of S. pneumoniae and suggest that high-level macrolide resistance is continuing to increase in most countries. [Copyright &y& Elsevier]

Abstract: A series of 3-keto-6-O-carbamoyl-11,12-cyclic thiocarbamate erythromycin A derivatives has been synthesized. The best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria. [Copyright &y& Elsevier]

This study aims to compare the resistance phenotypes conferred by various genes encoding enzymes that phosphorylate erythromycin. The mph genes were cloned into Escherichia coli AG100A susceptible to macrolides and ketolides following disruption of the AcrAB pump. An 882 bp sequence containing a premature stop codon, homologous to the three other previously described mph genes and present widely among Enterobacteriaceae, was found to confer resistance to erythromycin by phosphorylation. The mph(C) gene, as reported for mph(B), also conferred resistance to spiramycin. The mph(A) gene was unique in conferring resistance to azithromycin. The four investigated genes conferred resistance to telithromycin. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of ketolides containing heteroaryl groups that are linked to the erythronolide ring via a C6-carbazate functionality has been successfully synthesized. Careful modulation of the heteroaryl groups, the length and degree of saturation of the C6-carbazate linker, and the substituents present on each of the carbazate nitrogens led to compounds with potent activity against key bacterial respiratory pathogens. The best analogs of this series had in vitro and in vivo (sc dosing) profiles that were comparable to telithromycin. [Copyright &y& Elsevier]

Abstract: Synthesis of C12 des-methyl ketolide is developed featuring an intramolecular epoxide formation/elimination process to establish the C12 stereocenter. These ketolides are potent against several key respiratory pathogens, including erythromycin resistant erm- and mef-containing strains of Streptococcus pneumoniae. [Copyright &y& Elsevier]

Abstract: A novel series of C12 ethyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens, including those resistant to erythromycin. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with an ethyl group via chemical synthesis. From the C12 ethyl macrolide core, a series of C12 ethyl ketolides were prepared and tested for antibacterial activity against a panel of relevant clinical isolates. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria, whether resistance was due to ribosome methylation (erm) or efflux (mef). In particular, the C12 ethyl ketolides 4k,4s,4q,4m, and 4t showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. The in vivo efficacy of several C12 ethyl ketolides was demonstrated in a mouse infection model with Streptococcus pneumoniae as pathogen. [Copyright &y& Elsevier]

Abstract: A new type of ketolide bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and its analogues were prepared, and their antibacterial activities and pharmacokinetic properties were evaluated. We found that the introduction of an (R)-alkyl group between the amide and iminoether groups could improve the pharmacokinetic properties while maintaining the activity against erythromycin-resistant Streptococcus pneumoniae. Among the ketolides prepared with the (R)-alkyl group, compound 5p with an N-(3-quinoxalin-6-yl-propyl)-propionamide moiety was found to have in vivo efficacy comparable to CAM with potent in vitro antibacterial activities against the key respiratory pathogens including Haemophilus influenzae and erythromycin-resistant S. pneumoniae. [Copyright &y& Elsevier]