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Fighting resistant tuberculosis with old compounds: the carbapenem paradigm
INFECTION HOT TOPIC
10.1111/j.1469-0691.2011.03699.x
Fighting resistant tuberculosis with old compounds: the carbapenem paradigm
J. L. Mainardi
1,2,3,4
, J. E. Hugonnet1,2,3, L. Gutmann1,2,3,4 and M. Arthur1,2,3
1) Centre de Recherche des Cordeliers, LRMA, Equipe 12, Universite´ Paris Descartes, Sorbonne Paris Cite´, 2) Universite´ Pierre et Marie Curie, 3) INSERM and 4) AP-HP, Hoˆpital Europe´en Georges Pompidou, Paris, France E-mails: [email protected]; [email protected] Article published online: 13 October 2011
Despite intensive efforts to improve tuberculosis (TB) care and control, the global burden of TB is falling only slowly, and the evolution of drug resistance remains uncertain. According to the WHO, the estimated incidence in 2009 was 9.4 million new cases [1]. In recent years, TB treatment has become more complicated because of the emergence of multidrugresistant (MDR) TB, i.e. TB caused by strains resistant to isoniazid and rifampin. In 2009, an estimated 250 000 patients had MDR TB, representing 3.3% of new TB cases and up to 28% in certain countries of the former Soviet Union [1]. In 2008, the number of deaths caused by MDR TB was estimated to be 150 000. The emergence of extensively drugresistant (XDR) TB, defined by resistance to isoniazid and rifampin combined with additional resistance to a fluoroquinolone and at least 1 s line injectable agent (amikacin, kanamycin, or capreomycin), has been associated with increasing mortality (65–100%), as efficient therapy is not available [2]. By July 2010, 58 countries had reported at least one case of XDR TB [1]. These alarming data highlight the urgent need for new anti-TB drugs. Except for fluroquinolones, no novel anti-TB antibiotic has been introduced in the last 45 years. b-Lactams have not been considered to be useful drugs for the treatment of TB, because Mycobacterium tuberculosis naturally produces BlaC, an extended-spectrum class A b-lactamase [3]. However, older reports have shown that the combination of amoxycillin and clavulanic acid is bactericidal in vitro [4], an efficacy that can be accounted for by the recent demonstration that BlaC is irreversibly inactivated by clavulanic acid [3]. Reduction of the burden of M. tuberculosis in the sputum of patients treated with amoxycillin and clavulanic acid has been reported [5], but clinical assessments for the treatment of MDR TB are limited to anecdotal cases in which amoxycillin–clavulanic acid was used in association with second-line drugs [6]. Among the different classes of b-lactams, very recent data concerning carbapenems have opened new avenues towards
the potential use of this class in the treatment of TB, especially for MDR and XDR TB. Until recently, all b-lactams were thought to exclusively act on the active-site serine D,D-transpeptidases, the classic penicillin-binding proteins that catalyse the final cross-linking step of peptidoglycan synthesis. We have recently shown that these D,D-transpeptidases are bypassed by a novel family of polymerases, the active-site cysteine L,D-transpeptidases (Ldts), in b-lactam-resistant enterococci and in M. tuberculosis [7,8]. These enzymes are promising targets for the use of carbapenems, or for the development of anti-TB drugs belonging to this class, because the Ltds are responsible for the formation of 80% of the cross-links in M. tuberculosis, and these enzymes are irreversibly inactivated by carbapenems by the formation of covalent adducts [8,9]. Moreover, one of the five Ltds of M. tuberculosis (LdtMt2) is essential for virulence in a mouse model of acute infection [9]. Carbapenems are slowly hydrolysed by the b-lactamase BlaC [3], and one member of the carbapenem family, meropenem, has been reported to be uniformly active in vitro in association with clavulanic acid against a panel of XDR strains (meropenem MIC of <1 mg/L in the presence of 2.5 mg/L clavulanic acid [10]. Carbapenems may also have potential applications for the treatment of susceptible TB, because meropenem–clavulanic acid is active against non-replicative forms (‘dormant’ forms) of M. tuberculosis [10], which are difficult to eradicate even with isoniazid and rifampin. The adaptive response of M. tuberculosis during the transition from aerobic growth to stationary phase results in the activation of a ‘dormancy’ regulon, which includes genes that are likely to play an essential role in the long-term survival of the bacteria, and therefore encode potential targets for the development of sterilizing drugs. Among these genes, Rv0116c, which encodes LdtMt1, is upregulated 17-fold [11]. Thus, LdtMt1 could be an essential target accounting for the bactericidal activity of meropenem–clavulanic acid against dormant forms of M. tuberculosis in vitro [10]. In a mouse model, imipenem alone had antimycobacterial activity,
ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases
1756
Clinical Microbiology and Infection, Volume 17 Number 12, December 2011
although this carbapenem was less effective than isoniazid [12]. More recently, imipenem or meropenem associated with clavulanic acid was shown to improve the survival of mice infected with M. tuberculosis, although the combinations were less effective than isoniazid alone [13]. To date, the clinical experience with carbapenems is positive but very limited, and the b-lactams have only been used in combination with first-line and second-line drugs [12]. Despite very encouraging in vitro data highlighting carbapenems as promising agents for the treatment of resistant TB, there are several limitations, including the intravenous route of administration of all approved carbapenems (except for faropenem in Japan), the risks inherent in long-term vascular access, high costs, and very limited clinical experience. However, in vitro efficacy and the evolution of resistance justify the design of clinical studies to assess the efficacy of carbapenems in association with clavulanic acid in the treatment of MDR and XDR TB. The development of carbapenemrelated compounds may also lead to drugs that are not hydrolysed by BlaC and are appropriate for TB treatment.
Transparency Declaration Mainardi JL has received funds for speaking, consultancy, advisory board membership, travel from Pfizer, Novartis, Aventis, Astrazeneca, GSK, Janssen. L. Gutmann has received funds from Biomerieux and Cepheid. Mainardi JL has received research funding from Novartis and Merck Shape and Dohme (MSD).
CMI
2. Kliiman K, Altraja A. Predictors of poor treatment outcome in multiand extensively drug-resistant pulmonary TB. Eur Respir J 2009; 33: 1085–1094. 3. Hugonnet JE, Blanchard JS. Irreversible inhibition of the Mycobacterium tuberculosis beta-lactamase by clavulanate. Biochemistry 2007; 46: 11998–12004. 4. Cynamon MH, Palmer GS. In vitro activity of amoxicillin in combination with clavulanic acid against Mycobacterium tuberculosis. Antimicrob Agents Chemother 1983; 24: 429–431. 5. Chambers HF, Kocago¨z T, Sipit T, Turner J, Hopewell PC. Actvity of amoxicillin/clavulanate in patients with tuberculosis. Clin Infect Dis 1998; 26: 874–877. 6. Nadler JP, Berger J, Nord JA, Cofsky R, Saxena M. Amoxicillin–clavulanic acid for treating drug-resistant Mycobacterium tuberculosis. Chest 1991; 99: 1025–1026. 7. Mainardi JL, Villet R, Bugg TD, Mayer C, Arthur M. Evolution of peptidoglycan biosynthesis under the selective pressure of antibiotics in Gram-positive bacteria. FEMS Microbiol Rev 2008; 32: 386– 408. 8. Lavollay M, Arthur M, Fourgeaud M et al. The peptidoglycan of stationary phase Mycobacterium tuberculosis predominantly contains cross-links generated by L,D-transpeptidation. J Bacteriol 2008; 190: 4360–4366. 9. Gupta R, Lavollay M, Mainardi JL, Arthur M, Bishai WR, Lamichhane G. The Mycobacterium tuberculosis protein LdtMt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin. Nat Med 2010; 16: 466–469. 10. Hugonnet JE, Tremblay LW, Boshoff HI, Barry CE 3rd, Blanchard JS. Meropenem–clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science 2009; 323: 1215–1218. 11. Betts JC, Lukey PT, Robb LC, McAdam RA, Duncan K. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol, 2002; 43: 717–731. 12. Chambers HF, Turner J, Schecter GF, Kawamura M, Hopewell PC. Imipenem for treatment of tuberculosis in mice and humans. Antimicrob Agents Chemother 2005; 49: 2816–2821. 13. Veziris N, Truffot C, Mainardi JL, Jarlier V. Activity of carbapenems combined with clavulanate against murine tuberculosis. Antimicrob Agents Chemother 2011; 55: 2597–2600.
References 1. World Health Organization. Global tuberculosis control 2010. WHO report 2010. Available at: http://www.who.int/tb/en/ (last accessed 25 October 2011).
ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 17, 1755–1756
10.1111/j.1469-0691.2011.03699.x
Fighting resistant tuberculosis with old compounds: the carbapenem paradigm
J. L. Mainardi
1,2,3,4
, J. E. Hugonnet1,2,3, L. Gutmann1,2,3,4 and M. Arthur1,2,3
1) Centre de Recherche des Cordeliers, LRMA, Equipe 12, Universite´ Paris Descartes, Sorbonne Paris Cite´, 2) Universite´ Pierre et Marie Curie, 3) INSERM and 4) AP-HP, Hoˆpital Europe´en Georges Pompidou, Paris, France E-mails: [email protected]; [email protected] Article published online: 13 October 2011
Despite intensive efforts to improve tuberculosis (TB) care and control, the global burden of TB is falling only slowly, and the evolution of drug resistance remains uncertain. According to the WHO, the estimated incidence in 2009 was 9.4 million new cases [1]. In recent years, TB treatment has become more complicated because of the emergence of multidrugresistant (MDR) TB, i.e. TB caused by strains resistant to isoniazid and rifampin. In 2009, an estimated 250 000 patients had MDR TB, representing 3.3% of new TB cases and up to 28% in certain countries of the former Soviet Union [1]. In 2008, the number of deaths caused by MDR TB was estimated to be 150 000. The emergence of extensively drugresistant (XDR) TB, defined by resistance to isoniazid and rifampin combined with additional resistance to a fluoroquinolone and at least 1 s line injectable agent (amikacin, kanamycin, or capreomycin), has been associated with increasing mortality (65–100%), as efficient therapy is not available [2]. By July 2010, 58 countries had reported at least one case of XDR TB [1]. These alarming data highlight the urgent need for new anti-TB drugs. Except for fluroquinolones, no novel anti-TB antibiotic has been introduced in the last 45 years. b-Lactams have not been considered to be useful drugs for the treatment of TB, because Mycobacterium tuberculosis naturally produces BlaC, an extended-spectrum class A b-lactamase [3]. However, older reports have shown that the combination of amoxycillin and clavulanic acid is bactericidal in vitro [4], an efficacy that can be accounted for by the recent demonstration that BlaC is irreversibly inactivated by clavulanic acid [3]. Reduction of the burden of M. tuberculosis in the sputum of patients treated with amoxycillin and clavulanic acid has been reported [5], but clinical assessments for the treatment of MDR TB are limited to anecdotal cases in which amoxycillin–clavulanic acid was used in association with second-line drugs [6]. Among the different classes of b-lactams, very recent data concerning carbapenems have opened new avenues towards
the potential use of this class in the treatment of TB, especially for MDR and XDR TB. Until recently, all b-lactams were thought to exclusively act on the active-site serine D,D-transpeptidases, the classic penicillin-binding proteins that catalyse the final cross-linking step of peptidoglycan synthesis. We have recently shown that these D,D-transpeptidases are bypassed by a novel family of polymerases, the active-site cysteine L,D-transpeptidases (Ldts), in b-lactam-resistant enterococci and in M. tuberculosis [7,8]. These enzymes are promising targets for the use of carbapenems, or for the development of anti-TB drugs belonging to this class, because the Ltds are responsible for the formation of 80% of the cross-links in M. tuberculosis, and these enzymes are irreversibly inactivated by carbapenems by the formation of covalent adducts [8,9]. Moreover, one of the five Ltds of M. tuberculosis (LdtMt2) is essential for virulence in a mouse model of acute infection [9]. Carbapenems are slowly hydrolysed by the b-lactamase BlaC [3], and one member of the carbapenem family, meropenem, has been reported to be uniformly active in vitro in association with clavulanic acid against a panel of XDR strains (meropenem MIC of <1 mg/L in the presence of 2.5 mg/L clavulanic acid [10]. Carbapenems may also have potential applications for the treatment of susceptible TB, because meropenem–clavulanic acid is active against non-replicative forms (‘dormant’ forms) of M. tuberculosis [10], which are difficult to eradicate even with isoniazid and rifampin. The adaptive response of M. tuberculosis during the transition from aerobic growth to stationary phase results in the activation of a ‘dormancy’ regulon, which includes genes that are likely to play an essential role in the long-term survival of the bacteria, and therefore encode potential targets for the development of sterilizing drugs. Among these genes, Rv0116c, which encodes LdtMt1, is upregulated 17-fold [11]. Thus, LdtMt1 could be an essential target accounting for the bactericidal activity of meropenem–clavulanic acid against dormant forms of M. tuberculosis in vitro [10]. In a mouse model, imipenem alone had antimycobacterial activity,
ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases
1756
Clinical Microbiology and Infection, Volume 17 Number 12, December 2011
although this carbapenem was less effective than isoniazid [12]. More recently, imipenem or meropenem associated with clavulanic acid was shown to improve the survival of mice infected with M. tuberculosis, although the combinations were less effective than isoniazid alone [13]. To date, the clinical experience with carbapenems is positive but very limited, and the b-lactams have only been used in combination with first-line and second-line drugs [12]. Despite very encouraging in vitro data highlighting carbapenems as promising agents for the treatment of resistant TB, there are several limitations, including the intravenous route of administration of all approved carbapenems (except for faropenem in Japan), the risks inherent in long-term vascular access, high costs, and very limited clinical experience. However, in vitro efficacy and the evolution of resistance justify the design of clinical studies to assess the efficacy of carbapenems in association with clavulanic acid in the treatment of MDR and XDR TB. The development of carbapenemrelated compounds may also lead to drugs that are not hydrolysed by BlaC and are appropriate for TB treatment.
Transparency Declaration Mainardi JL has received funds for speaking, consultancy, advisory board membership, travel from Pfizer, Novartis, Aventis, Astrazeneca, GSK, Janssen. L. Gutmann has received funds from Biomerieux and Cepheid. Mainardi JL has received research funding from Novartis and Merck Shape and Dohme (MSD).
CMI
2. Kliiman K, Altraja A. Predictors of poor treatment outcome in multiand extensively drug-resistant pulmonary TB. Eur Respir J 2009; 33: 1085–1094. 3. Hugonnet JE, Blanchard JS. Irreversible inhibition of the Mycobacterium tuberculosis beta-lactamase by clavulanate. Biochemistry 2007; 46: 11998–12004. 4. Cynamon MH, Palmer GS. In vitro activity of amoxicillin in combination with clavulanic acid against Mycobacterium tuberculosis. Antimicrob Agents Chemother 1983; 24: 429–431. 5. Chambers HF, Kocago¨z T, Sipit T, Turner J, Hopewell PC. Actvity of amoxicillin/clavulanate in patients with tuberculosis. Clin Infect Dis 1998; 26: 874–877. 6. Nadler JP, Berger J, Nord JA, Cofsky R, Saxena M. Amoxicillin–clavulanic acid for treating drug-resistant Mycobacterium tuberculosis. Chest 1991; 99: 1025–1026. 7. Mainardi JL, Villet R, Bugg TD, Mayer C, Arthur M. Evolution of peptidoglycan biosynthesis under the selective pressure of antibiotics in Gram-positive bacteria. FEMS Microbiol Rev 2008; 32: 386– 408. 8. Lavollay M, Arthur M, Fourgeaud M et al. The peptidoglycan of stationary phase Mycobacterium tuberculosis predominantly contains cross-links generated by L,D-transpeptidation. J Bacteriol 2008; 190: 4360–4366. 9. Gupta R, Lavollay M, Mainardi JL, Arthur M, Bishai WR, Lamichhane G. The Mycobacterium tuberculosis protein LdtMt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin. Nat Med 2010; 16: 466–469. 10. Hugonnet JE, Tremblay LW, Boshoff HI, Barry CE 3rd, Blanchard JS. Meropenem–clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science 2009; 323: 1215–1218. 11. Betts JC, Lukey PT, Robb LC, McAdam RA, Duncan K. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol, 2002; 43: 717–731. 12. Chambers HF, Turner J, Schecter GF, Kawamura M, Hopewell PC. Imipenem for treatment of tuberculosis in mice and humans. Antimicrob Agents Chemother 2005; 49: 2816–2821. 13. Veziris N, Truffot C, Mainardi JL, Jarlier V. Activity of carbapenems combined with clavulanate against murine tuberculosis. Antimicrob Agents Chemother 2011; 55: 2597–2600.
References 1. World Health Organization. Global tuberculosis control 2010. WHO report 2010. Available at: http://www.who.int/tb/en/ (last accessed 25 October 2011).
ª2011 The Authors Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 17, 1755–1756