Grup B β-laktamazlar: Metallo β-laktamazlar
Özet
Metallo-β-laktamazlar (MBL’ler), β-laktam antibiyotiklerin tüm gruplarına karşı geniş direnç sağlayan enzimlerdir. Bu enzimler, aktif bölgelerinde çinko iyonu bulunduran ve Ambler sınıflandırmasına göre B sınıfı β-laktamazlar olarak tanımlanan metalloproteinlerdir. MBL’ler özellikle Pseudomonas aeruginosa, Acinetobacter baumannii ve Enterobacterales türlerinde karbapenem direncinin başlıca nedenidir. Genetik olarak taşınabilir elementlerle (plazmid, transpozon) yayılabilmeleri, küresel ölçekte hızla direnç artışına yol açmaktadır. MBL’ler yapılarına göre B1, B2 ve B3 alt sınıflarına ayrılır; en yaygın olan B1 grubuna IMP, VIM ve NDM tipleri dahildir. Bu enzimlerin aktif bölgelerindeki çinko iyonları, β-laktam halkasının hidrolizini katalize eder. Güncel klinik testlerde MBL saptanması için EDTA veya dipikolinik asit gibi şelatör bazlı fenotipik yöntemler kullanılmakta, ancak moleküler teknikler (PCR, sekanslama) daha yüksek duyarlılık sağlamaktadır. Karbapenem direncine neden olmaları nedeniyle MBL üreten suşlar tedavide ciddi zorluklar yaratır. Bu bakterilere karşı etkili antibiyotikler sınırlıdır; aztreonam-avibaktam gibi yeni kombinasyonlar umut verici görünmektedir. MBL’lerin yayılımının kontrolü, infeksiyon kontrol önlemleri ve antimikrobiyal direnç takibinin güçlendirilmesiyle mümkündür.
Metallo-β-lactamases (MBLs) are enzymes that confer broad-spectrum resistance to almost all β-lactam antibiotics. These metalloenzymes, classified as Ambler class B β-lactamases, contain zinc ions in their active sites, which catalyze the hydrolysis of the β-lactam ring. MBLs are major contributors to carbapenem resistance, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacterales species. Their genes are often located on mobile genetic elements such as plasmids and transposons, facilitating rapid global dissemination. Based on their structural characteristics, MBLs are divided into B1, B2, and B3 subclasses, with the B1 group-including IMP, VIM, and NDM types-being the most prevalent. Phenotypic detection methods using chelating agents such as EDTA or dipicolinic acid are commonly employed, while molecular techniques (e.g., PCR and sequencing) provide higher sensitivity and specificity. Due to their ability to hydrolyze carbapenems, infections caused by MBL-producing strains pose major therapeutic challenges. Treatment options remain limited, although novel combinations such as aztreonam–avibactam show promising activity. Controlling the spread of MBL-producing organisms requires strengthened infection control measures and continuous surveillance of antimicrobial resistance.
Referanslar
Bahr G, González LJ, Vila AJ. Metallo-betalactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design. Chem Rev. 2021;121(13):7957-8094. doi:10.1021/acs.chemrev.1c00138
Bush K, Jacoby GA. Updated functional classification of betalactamases. Antimicrob Agents Chemother. 2010;54(3):969-76. doi:10.1128/AAC.01009-09.
Queenan AM, Bush K. Carbapenemases: the versatile betalactamases. Clin Microbiol Rev. 2007;20(3):440–58. doi: 10.1128/CMR.00001-07.
Tooke CL, Hinchliffe P, Bragginton CF, et al. Beta-lactamases and betalactamase inhibitors in the 21st century. J Mol Biol. 2019;431(18):3472-500. doi:10.1016/j.jmb.2019.04.002.
Boyd SE, Livermore DM, Hooper DC, Hope WW. Metallo-betaLactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline. Antimicrob Agents Chemother. 2020;64(10):e00397-20. doi:10.1128/AAC.00397-20
Cui X, Zhang H, Du H. Carbapenemases in Enterobacteriaceae: Detection and Antimicrobial Therapy. Front Microbiol. 2019 Aug 20;10:1823. doi:10.3389/fmicb.2019.01823
Grabein B, Arhin FF, Daikos GL, Moore LSP, Balaji V, Baillon-Plot N. Navigating the current treatment landscape of metallo-betalactamase-producing Gram-negative infections: what are the limitations? Infect Dis Ther. 2024;13(11):2423-2447. doi:10.1007/s40121-024-01044-8
Tan X, Kim HS, Baugh K, Huang Y, Kadiyala N, Wences M, Singh N, Wenzler E, Bulman ZP. Therapeutic options for metallo-betalactamase-producing Enterobacterales. Infect Drug Resist. 2021;14:125-142. doi:10.2147/IDR.S246174
Wu W, Feng Y, Tang G, Qiao F, McNally A, Zong Z. NDM metallo-betalactamases and their bacterial producers in health care settings. Clin Microbiol Rev. 2019;32(2):e00115-18. doi:10.1128/CMR.00115-18.
Bahr G, González LJ, Vila AJ. Metallo- β-lactamases and a tug-of-war for the available zinc at the host–pathogen interface. Curr Opin Chem Biol. 2022;66:102103. doi: 10.1016/j.cbpa.2021.102103.
Kang SJ, Kim DH, Lee BJ. Metallo-β-lactamase inhibitors: A continuing challenge for combating antibiotic resistance. Biophysical Chemistry. 2024;309:107228
Sangiorgio G, Calvo M, Stefani S. Aztreonam and avibactam combination therapy for metallo-β-lactamase-producing gram-negative bacteria: a narrative review. Clin Microbiol Infect. 2025;31(7):971–978. doi:10.1016/j.cmi.2024.11.006.
Referanslar
Bahr G, González LJ, Vila AJ. Metallo-betalactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design. Chem Rev. 2021;121(13):7957-8094. doi:10.1021/acs.chemrev.1c00138
Bush K, Jacoby GA. Updated functional classification of betalactamases. Antimicrob Agents Chemother. 2010;54(3):969-76. doi:10.1128/AAC.01009-09.
Queenan AM, Bush K. Carbapenemases: the versatile betalactamases. Clin Microbiol Rev. 2007;20(3):440–58. doi: 10.1128/CMR.00001-07.
Tooke CL, Hinchliffe P, Bragginton CF, et al. Beta-lactamases and betalactamase inhibitors in the 21st century. J Mol Biol. 2019;431(18):3472-500. doi:10.1016/j.jmb.2019.04.002.
Boyd SE, Livermore DM, Hooper DC, Hope WW. Metallo-betaLactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline. Antimicrob Agents Chemother. 2020;64(10):e00397-20. doi:10.1128/AAC.00397-20
Cui X, Zhang H, Du H. Carbapenemases in Enterobacteriaceae: Detection and Antimicrobial Therapy. Front Microbiol. 2019 Aug 20;10:1823. doi:10.3389/fmicb.2019.01823
Grabein B, Arhin FF, Daikos GL, Moore LSP, Balaji V, Baillon-Plot N. Navigating the current treatment landscape of metallo-betalactamase-producing Gram-negative infections: what are the limitations? Infect Dis Ther. 2024;13(11):2423-2447. doi:10.1007/s40121-024-01044-8
Tan X, Kim HS, Baugh K, Huang Y, Kadiyala N, Wences M, Singh N, Wenzler E, Bulman ZP. Therapeutic options for metallo-betalactamase-producing Enterobacterales. Infect Drug Resist. 2021;14:125-142. doi:10.2147/IDR.S246174
Wu W, Feng Y, Tang G, Qiao F, McNally A, Zong Z. NDM metallo-betalactamases and their bacterial producers in health care settings. Clin Microbiol Rev. 2019;32(2):e00115-18. doi:10.1128/CMR.00115-18.
Bahr G, González LJ, Vila AJ. Metallo- β-lactamases and a tug-of-war for the available zinc at the host–pathogen interface. Curr Opin Chem Biol. 2022;66:102103. doi: 10.1016/j.cbpa.2021.102103.
Kang SJ, Kim DH, Lee BJ. Metallo-β-lactamase inhibitors: A continuing challenge for combating antibiotic resistance. Biophysical Chemistry. 2024;309:107228
Sangiorgio G, Calvo M, Stefani S. Aztreonam and avibactam combination therapy for metallo-β-lactamase-producing gram-negative bacteria: a narrative review. Clin Microbiol Infect. 2025;31(7):971–978. doi:10.1016/j.cmi.2024.11.006.
