Meropenem-Clavulanate Is Effective Against Extensively Drug-Resistant
            <i>Mycobacterium tuberculosis</i>

Hugonnet, Jean-Emmanuel; Tremblay, L.W.; Boshoff, Helena I.; Barry, Clifton E.; Blanchard, John S.

doi:10.1126/science.1167498

Cited by 449 publications

(520 citation statements)

References 18 publications

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“…Further, carbapenems are active against M tuberculosis in vitro, and clavulanate, an irreversible inhibitor of BlaC, further enhances the activity of carbapenems. 358,359 The combination of a carbapenem and a penicillin might also have additive or synergistic effects. 360 To examine the activity of a carbapenem-penicillin-clavulanate combin ation in vivo, a recent phase 2A proof-of-concept trial was done.…”

Section: β-Lactamsmentioning

confidence: 99%

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Dheda

Gumbo

Maartens

et al. 2017

The Lancet Respiratory Medicine

521

474

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Section: β-Lactamsmentioning

confidence: 99%

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Dheda

Gumbo

Maartens

et al. 2017

The Lancet Respiratory Medicine

521

474

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“…Carbapenems were recently recognized as promising agents in the treatment of tuberculosis because these drugs are bactericidal against extensively drug-resistant (XDR) strains of M. tuberculosis (7). Carbapenems were active in association with clavulanic acid, a ␤-lactamase inhibitor that irreversibly inactivates the broad-spectrum BlaC ␤-lactamase constitutively produced by members of this species (8).…”

mentioning

confidence: 99%

Inactivation Kinetics of a New Target of β-Lactam Antibiotics

Triboulet

Arthur

Mainardi

et al. 2011

Journal of Biological Chemistry

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Peptidoglycan is predominantly cross-linked by serine DD-transpeptidases in most bacterial species. The enzymes are the essential targets of ␤-lactam antibiotics. However, unrelated cysteine LD-transpeptidases have been recently recognized as a predominant mode of peptidoglycan cross-linking in Mycobacterium tuberculosis and as a bypass mechanism conferring resistance to all ␤-lactams, except carbapenems such as imipenem, in Enterococcus faecium. Investigation of the mechanism of inhibition of this new ␤-lactam target showed that acylation of the E. faecium enzyme (Ldt fm ) by imipenem is irreversible. Using fluorescence kinetics, an original approach was developed to independently determine the catalytic constants for imipenem binding (k 1 ‫؍‬ 0.061 M ؊1 min ؊1 ) and acylation (k inact ‫؍‬ 4.5 min ؊1 ). The binding step was limiting at the minimal drug concentration required for bacterial growth inhibition. The Michaelis complex was committed to acylation because its dissociation was negligible. The emergence of imipenem resistance involved substitutions in Ldt fm that reduced the rate of formation of the non-covalent complex but only marginally affected the efficiency of the acylation step. The methods described in this study will facilitate development of new carbapenems active on extensively resistant M. tuberculosis.␤-Lactam antibiotics entered clinical trials in 1941 and have become and remained the most widely used family of drugs for the treatment of severe infections. The success of these molecules as therapeutic agents originates from a combination of properties, including low toxicity, excellent bioavailability, and broad-spectrum bactericidal activity. The latter property is accounted for by the conservation of the target, the active-site serine DD-transpeptidases, thought to catalyze an essential step in cell wall synthesis in all peptidoglycan-containing bacteria (1). The discovery of hundreds of ␤-lactams and of ␤-lactamase inhibitors has made it possible to partially compensate for the erosion of antibacterial activity due to the emergence of various mechanisms of resistance. In Gram-negative bacteria, these mechanisms mostly involve the production of ␤-lactamases, often associated with decreased outer membrane permeability and drug efflux. In Gram-positive bacteria, ␤-lactamase production is also frequent, but modification of the DD-transpeptidases is the clinically relevant mechanism in important pathogens, such as Staphylococcus aureus, Streptococcus pneumoniae, and the enterococci. More recently, bypass of the DD-transpeptidases by a novel class of peptidoglycan polymerases, the LDtranspeptidases, has been shown to convey high level resistance to all ␤-lactams, except the carbapenems, in mutants of Enterococcus faecium selected in vitro (2). Transpeptidases of the DD and LD specificities are structurally unrelated, contain different active-site nucleophiles (Ser versus Cys, respectively), and catalyze formation of different peptidoglycan cross-links (433 versus 333, respectively) (3). The two...

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“…L'analyse a ensuite été étendue à une série de 13 isolats cliniques ultrarésistants provenant du Korean Institute of Tuberculosis à Séoul (Corée du Sud) [8]. Les concentrations minimales inhibitrices (CMI) ont été déterminées par la méthode de microdilution en utilisant des concentrations fixes d'acide clavulanique [9]. Des variations de réponse aux péni cillines et aux céphalosporines (données non montrées) sont observées entre les souches mais la combinaison comprenant le méropénème est active sur toutes les souches (Tableau I …”

Section: Inhibition De Launclassified

“…Cela s'explique par l'action inhibitrice de l'acide clavulanique sur la β-lactamase BlaC combiné au fait que le méropénème est un mauvais substrat de l'enzyme [9]. Le méro-pénème peut donc atteindre sa cible, avec pour conséquence l'interruption de la polymérisation du peptidoglycane, entraînant un arrêt de la croissance des bactéries et leur mort.…”

Section: Les Ld-transpeptidases Une Cible Du Méropénème Chez Les Founclassified

“…Cette découverte offre une perspective thérapeutique pour les patients infectés par des souches ultrarésistantes. Les essais cliniques ont débuté cette année en Corée du Sud, en collaboration avec Clifton Barry du National Institute of Allergy and Infectious Diseases ( Washington, DC, États-Unis), ainsi qu'en Afrique du Sud, en collaboration avec Brian Currie du Centre médical Montefiore (New York, États-Unis) (détaillé dans [9] …”

Section: Premiers Essais Cliniquesunclassified

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Meropenem-Clavulanate Is Effective Against Extensively Drug-Resistant Mycobacterium tuberculosis

Cited by 449 publications

References 18 publications

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Inactivation Kinetics of a New Target of β-Lactam Antibiotics

Une thérapie prometteuse contre les souches ultrarésistantes deM. tuberculosis

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