Ketolides lack inducibility properties of MLS(B) resistance phenotype

Bonnefoy, Alain; Girard, Anne-Marie; Agouridas, Constantin; Chantot, J F

doi:10.1093/jac/40.1.85

Cited by 173 publications

(69 citation statements)

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“…Macrolides with the cladinose group can induce MLS B , while the ketolide counterparts do not (2). However, ketolides have not been effective in strains constitutively expressing MLS resistance (MLS B ) (20), and considered together with the results of this study, this finding may suggest that TB ribosomes are constitutively methylated or that requirements for induction differ.…”

Section: Discussionmentioning

confidence: 59%

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

Falzari

Zhu

Pan

et al. 2005

Antimicrob Agents Chemother

201

246

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Existing macrolides have never shown definitive clinical efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved in macrolide resistance in Mycobacterium tuberculosis, a mechanism that newer macrolides have been designed to overcome in gram-positive bacteria. Therefore, selected macrolides and ketolides (descladinose) with substitutions at positions 9, 11,12, and 6 were assessed for activity against M. tuberculosis, and those with MICs of <4 M were evaluated for cytotoxicity to Vero cells and J774A.1 macrophages. Several compounds with 9-oxime substitutions or aryl substitutions at position 6 or on 11,12 carbamates or carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, macrolides demonstrated superior activity. Four compounds with low MICs and low cytotoxicity also effected significant reductions in CFU in infected macrophages. Active compounds were assessed for tolerance and the ability to reduce CFU in the lungs of BALB/c mice in an aerosol infection model. A substituted 11,12 carbazate macrolide demonstrated significant dose-dependent inhibition of M. tuberculosis growth in mice, with a 10-to 20-fold reduction of CFU in lung tissue. Structure-activity relationships, some of which are unique to M. tuberculosis, suggest several synthetic directions for further improvement of antituberculosis activity. This class appears promising for yielding a clinically useful agent for tuberculosis.Tuberculosis (TB) has been recognized as a major public health problem worldwide, exacerbated greatly by the human immunodeficiency virus pandemic. The length and complexity of antibiotic therapy for tuberculosis and the emergence of multidrug-resistant strains make a compelling case for the development of new efficacious anti-TB drugs.The development of new members of classes of established antibiotics, such as the macrolides, which already possess many desirable pharmacological properties, is one approach to rapidly add new drugs to the existing anti-TB armamentarium.Although they are antibiotics of choice for several respiratory pathogens and have demonstrated efficacy in other mycobacterioses, such as leprosy (6,15,17) and Mycobacterium avium (14,26,27) infections, the macrolides developed to date have lacked potency against the tubercle bacillus (24). The clinical use of clarithromycin in treating tuberculosis is limited to multiple-drug-resistant cases in which there are few remaining treatment options (21).The current development goal for macrolides has been primarily to overcome ribosome modification and drug efflux, the major mechanisms of resistance to this antibiotic class (22). Methylation of A2058, located in the peptidyl transferase loop of domain V of the 23S rRNA subunit, by specific methylases (erm) decreases macrolide binding affinity, rendering the organisms resistant to macrolides, lincosamides, and streptogramins, known as the MLS B phenotype (28,29). Macrolides in which the cladinose group is replaced with a keto group (ketolides) avoid efflux-med...

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Section: Discussionmentioning

confidence: 59%

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

Falzari

Zhu

Pan

et al. 2005

Antimicrob Agents Chemother

201

246

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“…Their key features include a 14‐membered macrolactone, the replacement of the C3 cladinose sugar by a keto group, a cyclic carbamate and an extended alkyl‐aryl side chain (Figure 11). The C3 keto group gives rise to potent activity against strains with Erm‐mediated inducible resistance and surmounts resistance through efflux 63. It also removes some of the steric hindrance around the desosamine sugar, which allows it to reposition itself when binding to monomethylated ribosomes 64.…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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“…A great deal of interest has been focused on the ketolides, partly because they are considered poor or weak inducers of erm genes in Gram-positive pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes (18,42,459). Another advantage of ketolides is that ribosome modification by erm monomethylases does not confer high-level resistance to these agents in some organisms (220).…”

Section: Inhibition Of Protein Synthesismentioning

confidence: 99%

Antimicrobial Susceptibility Testing, Drug Resistance Mechanisms, and Therapy of Infections with Nontuberculous Mycobacteria

2012

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SUMMARY Within the past 10 years, treatment and diagnostic guidelines for nontuberculous mycobacteria have been recommended by the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA). Moreover, the Clinical and Laboratory Standards Institute (CLSI) has published and recently (in 2011) updated recommendations including suggested antimicrobial and susceptibility breakpoints. The CLSI has also recommended the broth microdilution method as the gold standard for laboratories performing antimicrobial susceptibility testing of nontuberculous mycobacteria. This article reviews the laboratory, diagnostic, and treatment guidelines together with established and probable drug resistance mechanisms of the nontuberculous mycobacteria.

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Ketolides lack inducibility properties of MLS(B) resistance phenotype

Cited by 173 publications

References 0 publications

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

In Vitro and In Vivo Activities of Macrolide Derivatives against Mycobacterium tuberculosis

Targeting Antibiotic Resistance

Antimicrobial Susceptibility Testing, Drug Resistance Mechanisms, and Therapy of Infections with Nontuberculous Mycobacteria

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