Ribosome affinity and the prolonged molecular postantibiotic effect of cethromycin (ABT-773) in Haemophilus influenzae

Cao, Zhongcheng; Zhong, Ping; Ruan, Xiaoan; Merta, Phil; Capobianco, John O.; Flamm, Robert K.; Nilius, Angela M.

doi:10.1016/j.ijantimicag.2004.04.013

Cited by 9 publications

(3 citation statements)

References 24 publications

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“…4B). In agreement with this conclusion, the clinical macrolide candidates carrying extended alkyl-aryl side chains, exhibit a prolonged postantibiotic effect: that is, delayed regrowth of bacteria following exposure to antibiotic (3,(33)(34)(35). Previous binding studies have suggested that TEL, an example of a drug with an extended side chain (Fig.…”

Section: Discussionsupporting

confidence: 64%

Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics

Svetlov

Vázquez‐Laslop

Mankin

2017

Proc. Natl. Acad. Sci. U.S.A.

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Antibiotics can cause dormancy (bacteriostasis) or induce death (cidality) of the targeted bacteria. The bactericidal capacity is one of the most important properties of antibacterial agents. However, the understanding of the fundamental differences in the mode of action of bacteriostatic or bactericidal antibiotics, especially those belonging to the same chemical class, is very rudimentary. Here, by examining the activity and binding properties of chemically distinct macrolide inhibitors of translation, we have identified a key difference in their interaction with the ribosome, which correlates with their ability to cause cell death. While bacteriostatic and bactericidal macrolides bind in the nascent peptide exit tunnel of the large ribosomal subunit with comparable affinities, the bactericidal antibiotics dissociate from the ribosome with significantly slower rates. The sluggish dissociation of bactericidal macrolides correlates with the presence in their structure of an extended alkyl-aryl side chain, which establishes idiosyncratic interactions with the ribosomal RNA. Mutations or chemical alterations of the rRNA nucleotides in the drug binding site can protect cells from macrolide-induced killing, even with inhibitor concentrations that significantly exceed those required for cell growth arrest. We propose that the increased translation downtime due to slow dissociation of the antibiotic may damage cells beyond the point where growth can be reinitiated upon the removal of the drug due to depletion of critical components of the gene-expression pathway.

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Section: Discussionsupporting

confidence: 64%

Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics

Svetlov

Vázquez‐Laslop

Mankin

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…43 Compared with erythromycin, cethromycin displays higher binding affinity for H. influenzae ribosomes, faster intracellular accumulation rates, slower dissociation from the cell, and a much longer postantibiotic effect. 54 Although the tighter binding of cethromycin does not lead to faster inhibition of protein synthesis, it is thought that this characteristic allows for potent activity in the face of the efflux pump activity and the outer membrane permeability barrier of H. influenzae. 54 One study established that cethromycin and azithromycin have similar activity against H. influenzae, with an MIC 50 of 31,42,43 0.002-4.0 0.004-0.016 0.008-0.03 Penicillin resistant 31,42,43 0.002-2.0 0.004-0.03 0.03-0.125 Macrolide susceptible 31,42 ≤ 0.0005-0.03 0.0001-0.008 0.002-0.016 Macrolide resistant erm 31,42,44 ≤ 0.002-4.0 0.004-0.03 0.015-0.125 mef 31,42,44 ≤ 0.002-0.5 0.004-0.063 0.12-0.125 erm and mef 31,44 ≤ 0.002-0.5 0.06-0.063 0.25-0.5…”

Section: Gram-positive Activitymentioning

confidence: 99%

Cethromycin: A Promising New Ketolide Antibiotic for Respiratory Infections

2010

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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 beta-lactam and macrolide classes.

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“…Die Wirksamkeit ge− genüber Haemophilus influenzae ist mit der von Makroliden ver− gleichbar. Cethromycin verfügt ähnlich wie Telithromycin über einen im Vergleich zu Erythromycin verlängerten postantibioti− schen Effekt, was durch die höhere Bindungsaffinität an der 50S Untereinheit der Ribosomen zustande kommt [13].…”

Section: Cethromycin ± Ein Neues Orales Ketolid Mit Ungewisser Zukunftunclassified

Neue Antibiotika zur Therapie von Atemwegsinfektionen

Kruse¹,

Stahlmann²

2006

Pneumologie

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The need for new antibiotics is ongoing in view of manifold resistance developments. The resistance of Streptococcus pneumoniae against macrolides and penicillins in the USA already amounts to more than 30 %. The approval of new antibiotics, particularly those with a new mode of action, has been decreasing over the past years which is anticipated to result in a lack of resourceful therapy options in the future. Some new substances with good in vitro activity against S. pneumoniae have turned out to raise safety issues as shown for a number of quinolones. Likewise daptomycin, a lipopeptide with a new mechanism of action, did not show satisfying results due to its inactivation by surfactant. Established quinolones are levofloxacin and moxifloxacin, the latter being available as i. v. formulation since 2002. For ketolides, telithromycin (oral) and for azalides azithromycin (since 2005 as i. v. formulation) are available for antimicrobial therapy. Linezolid is the only approved oxazolidinone. Tigecycline, a tetracycline derivate, will be approved in 2006 in Germany. The latest approval regarding carbapenems was ertapenem in 2003, while doripenem, a new antibiotic from this group, is still under clinical development.

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Ribosome affinity and the prolonged molecular postantibiotic effect of cethromycin (ABT-773) in Haemophilus influenzae

Cited by 9 publications

References 24 publications

Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics

Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics

Cethromycin: A Promising New Ketolide Antibiotic for Respiratory Infections

Neue Antibiotika zur Therapie von Atemwegsinfektionen

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