Penisilin Bağlayan Proteinlere Bağlı Direnç
Özet
Penisilin bağlayan proteinler (PBP’ler), bakteriyel hücre duvarı sentezinin temel enzimleridir ve β-laktam antibiyotiklerin başlıca hedefini oluştururlar. PBP’ler, moleküler ağırlık ve enzimatik işlevlerine göre; çift işlevli sınıf A PBP’ler, yalnızca transpeptidaz aktivitesine sahip sınıf B PBP’ler ve düşük moleküler ağırlıklı sınıf C PBP’ler olarak sınıflandırılırlar. β-laktam antibiyotikler, bu proteinlerin aktif bölgesine kovalent olarak bağlanarak peptidoglikan sentezini inhibe ederler. Ancak bakteriler, PBP’lerdeki değişiklikleri içeren çeşitli mekanizmalar ile β-laktam antibiyotiklere karşı direnç geliştirebilirler. Bu mekanizmalar arasında düşük afiniteli varyantların üretimi, aşırı ifade, mozaik genlerin kazanımı veya yapısal genlerdeki mutasyonlar yer almaktadır. Gram pozitif bakterilerde başlıca direnç mekanizması, PBP değişiklikleri iken, gram negatif bakterilerde β-laktamazlar ön plandadır. Bununla birlikte, PBP değişiklikleri bu bakterilerde de artan öneme sahiptir. Bu derlemede, farklı bakteri türlerinde PBP’lerin yapısı, sınıflandırılması ve antibiyotik direnci ile ilişkisi güncel literatür ışığında irdelenmiştir.
Penicillin-binding proteins (PBPs) are key enzymes in bacterial cell wall synthesis and represent the primary targets of β-lactam antibiotics. PBPs are classified based on their molecular weight and enzymatic function into three groups: bifunctional class A PBPs, class B PBPs with only transpeptidase activity, and low-molecular-weight class C PBPs. β-lactam antibiotics inhibit peptidoglycan synthesis by covalently binding to the active site of these proteins. However, bacteria can develop resistance to β-lactam antibiotics through various mechanisms, including modifications in penicillin-binding proteins (PBPs). These mechanisms include the production of low-affinity variants, overexpression, acquisition of mosaic genes or mutations in structural genes. In gram positive bacteria, the primary resistance mechanism involves PBP modifications, whereas in gram negative bacteria, β-lactamase production is more prominent. Nevertheless, PBP modifications are increasingly recognized as important contributors to resistance in gram negative bacteria as well. In this review, the structure, classification, and association of PBPs with antibiotic resistance in different bacterial species have been reviewed in light of current literature.
Referanslar
Dabhi M, Patel R, Shah V, Soni R, Saraf M, Raural R, et al. Penicillin-binding proteins: the master builders and breakers of bacterial cell walls and its interaction with β-lactam antibiotics. J Proteins Proteom. 2024; 15:215–232. https://doi.org/10.1007/s42485-024-00135-x
Gülay Z. Hücre Duvar Sentezini Etkileyen Antibakteriyeller. ANKEM Dergisi. 2003; 17(3):192-204.
Sethuvel DPM, Bakthavatchalam YD, Karthik M, Irulappan M, Shrivastava R, Periasamy H, et al. β-Lactam Resistance in ESKAPE Pathogens Mediated Through Modifications in Penicillin-Binding Proteins: An Overview. Infect Dis Ther. 2023;12(3): 829-841. https://doi.org/10.1007/s40121-023-00771-8
Sauvage E, Kerff F, Terrak M, Ayala JA, Charlier P. The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev. 2008; 32(2): 234-58. https://doi.org/10.1111/j.1574-6976.2008.00105.x.
Sauvage E, Terrak M. Glycosyltransferases and Transpeptidases/Penicillin-Binding Proteins: Valuable Targets for New Antibacterials. Antibiotics (Basel). 2016; 5(1): 12. https://doi.org/10.3390/antibiotics5010012
Cochrane SA, Lohans CT. Breaking down the cell wall: Strategies for antibiotic discovery targeting bacterial transpeptidases. Eur J Med Chem. 2020; 194:112262. https://doi.org/10.1016/j.ejmech.2020.112262
Spratt BG. Properties of the penicillin-binding proteins of Escherichia coli K12. Eur J Biochem. 1977;72(2):341-52. https://doi.org/10.1111/j.1432-1033.1977.tb11258.x
Sahare P, Moon A. Penicillin Binding Proteins: An Insight Into Novel Antibacterial Drug Target. Int. J. Eng. Sci. Res. 2014; 5: 13–23.
Shaku M, Ealand C, Matlhabe O, Lala R, Kana BD. Peptidoglycan biosynthesis and remodeling revisited. Adv Appl Microbiol. 2020;112:67-103. https://doi.org/10.1016/bs.aambs.2020.04.001
Juan C, Torrens G, Barceló IM, Oliver A. Interplay between Peptidoglycan Biology and Virulence in Gram-Negative Pathogens. Microbiol Mol Biol Rev. 2018;82(4):e00033-18. https://doi.org/10.1128/MMBR.00033-18
Lambert PA. Bacterial resistance to antibiotics: modified target sites. Adv Drug Deliv Rev. 2005;57(10):1471-85. https://doi.org/10.1016/j.addr.2005.04.003
Baran A, Kwiatkowska A, Potocki L. Antibiotics and Bacterial Resistance-A Short Story of an Endless Arms Race. Int J Mol Sci. 2023; 24(6): 5777. https://doi.org/10.3390/ijms24065777
Opal SM, Pop-Vicas A. Molecular mechanisms of antibiotic resistance in bacteria. In: JE Bennett, R Dolin, MJ Blaser. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Philadelphia, PA: Elsevier, Inc; 2020: 222-239.e3.
Straume D, Piechowiak KW, Kjos M, Håvarstein LS. Class A PBPs: It is time to rethink traditional paradigms. Mol Microbiol. 2021;116(1):41-52. https://doi.org/10.1111/mmi.14714
Zapun A, Contreras-Martel C, Vernet T. Penicillin-binding proteins and beta-lactam resistance. FEMS Microbiol Rev. 2008; 32(2): 361-85. https://doi.org/10.1111/j.1574-6976.2007.00095.x
Yu D, Guo D, Zheng Y, Yang Y. A review of penicillin binding protein and group A Streptococcus with reduced-β-lactam susceptibility. Front Cell Infect Microbiol. 2023; 13: 1117160. https://doi.org/10.3389/fcimb.2023.1117160
Lai CKC, Ng RWY, Leung SSY, Hui M, Ip M. Overcoming the rising incidence and evolving mechanisms of antibiotic resistance by novel drug delivery approaches - An overview. Adv Drug Deliv Rev. 2022;181:114078. https://doi.org/10.1016/j.addr.2021.114078
Georgopapadakou NH, Smith SA, Bonner DP. Penicillin-binding proteins in a Staphylococcus aureus strain resistant to specific beta-lactam antibiotics. Antimicrob Agents Chemother. 1982;22(1):172-5. https://doi.org/10.1128/AAC.22.1.172
Cetinkaya Y, Falk P, Mayhall CG. Vancomycin-resistant enterococci. Clin Microbiol Rev. 2000; 13(4): 686-707. https://doi.org/10.1128/CMR.13.4.686
Gagetti P, Bonofiglio L, García Gabarrot G, Kaufman S, Mollerach M, Vigliarolo L, et al. Resistance to β-lactams in enterococci. Rev Argent Microbiol. 2019; 51(2):179-183. https://doi.org/10.1016/j.ram.2018.01.007
Gawryszewska I, Żabicka D, Hryniewicz W, Sadowy E. Penicillin-Resistant, Ampicillin-Susceptible Enterococcus faecalis in Polish Hospitals. Microb Drug Resist. 2021;27(3):291-300. https://doi.org/10.1089/mdr.2019.0504
Sakalauskienė GV, Malcienė L, Stankevičius E, Radzevičienė A. Unseen Enemy: Mechanisms of Multidrug Antimicrobial Resistance in Gram-Negative ESKAPE Pathogens. Antibiotics (Basel). 2025;14(1):63. https://doi.org/10.3390/antibiotics14010063
Glen KA, Lamont IL. Penicillin-binding protein 3 sequence variations reduce susceptibility of Pseudomonas aeruginosa to β-lactams but inhibit cell division. J Antimicrob Chemother. 2024;79(9):2170-2178. https://doi.org/10.1093/jac/dkae203
Referanslar
Dabhi M, Patel R, Shah V, Soni R, Saraf M, Raural R, et al. Penicillin-binding proteins: the master builders and breakers of bacterial cell walls and its interaction with β-lactam antibiotics. J Proteins Proteom. 2024; 15:215–232. https://doi.org/10.1007/s42485-024-00135-x
Gülay Z. Hücre Duvar Sentezini Etkileyen Antibakteriyeller. ANKEM Dergisi. 2003; 17(3):192-204.
Sethuvel DPM, Bakthavatchalam YD, Karthik M, Irulappan M, Shrivastava R, Periasamy H, et al. β-Lactam Resistance in ESKAPE Pathogens Mediated Through Modifications in Penicillin-Binding Proteins: An Overview. Infect Dis Ther. 2023;12(3): 829-841. https://doi.org/10.1007/s40121-023-00771-8
Sauvage E, Kerff F, Terrak M, Ayala JA, Charlier P. The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev. 2008; 32(2): 234-58. https://doi.org/10.1111/j.1574-6976.2008.00105.x.
Sauvage E, Terrak M. Glycosyltransferases and Transpeptidases/Penicillin-Binding Proteins: Valuable Targets for New Antibacterials. Antibiotics (Basel). 2016; 5(1): 12. https://doi.org/10.3390/antibiotics5010012
Cochrane SA, Lohans CT. Breaking down the cell wall: Strategies for antibiotic discovery targeting bacterial transpeptidases. Eur J Med Chem. 2020; 194:112262. https://doi.org/10.1016/j.ejmech.2020.112262
Spratt BG. Properties of the penicillin-binding proteins of Escherichia coli K12. Eur J Biochem. 1977;72(2):341-52. https://doi.org/10.1111/j.1432-1033.1977.tb11258.x
Sahare P, Moon A. Penicillin Binding Proteins: An Insight Into Novel Antibacterial Drug Target. Int. J. Eng. Sci. Res. 2014; 5: 13–23.
Shaku M, Ealand C, Matlhabe O, Lala R, Kana BD. Peptidoglycan biosynthesis and remodeling revisited. Adv Appl Microbiol. 2020;112:67-103. https://doi.org/10.1016/bs.aambs.2020.04.001
Juan C, Torrens G, Barceló IM, Oliver A. Interplay between Peptidoglycan Biology and Virulence in Gram-Negative Pathogens. Microbiol Mol Biol Rev. 2018;82(4):e00033-18. https://doi.org/10.1128/MMBR.00033-18
Lambert PA. Bacterial resistance to antibiotics: modified target sites. Adv Drug Deliv Rev. 2005;57(10):1471-85. https://doi.org/10.1016/j.addr.2005.04.003
Baran A, Kwiatkowska A, Potocki L. Antibiotics and Bacterial Resistance-A Short Story of an Endless Arms Race. Int J Mol Sci. 2023; 24(6): 5777. https://doi.org/10.3390/ijms24065777
Opal SM, Pop-Vicas A. Molecular mechanisms of antibiotic resistance in bacteria. In: JE Bennett, R Dolin, MJ Blaser. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Philadelphia, PA: Elsevier, Inc; 2020: 222-239.e3.
Straume D, Piechowiak KW, Kjos M, Håvarstein LS. Class A PBPs: It is time to rethink traditional paradigms. Mol Microbiol. 2021;116(1):41-52. https://doi.org/10.1111/mmi.14714
Zapun A, Contreras-Martel C, Vernet T. Penicillin-binding proteins and beta-lactam resistance. FEMS Microbiol Rev. 2008; 32(2): 361-85. https://doi.org/10.1111/j.1574-6976.2007.00095.x
Yu D, Guo D, Zheng Y, Yang Y. A review of penicillin binding protein and group A Streptococcus with reduced-β-lactam susceptibility. Front Cell Infect Microbiol. 2023; 13: 1117160. https://doi.org/10.3389/fcimb.2023.1117160
Lai CKC, Ng RWY, Leung SSY, Hui M, Ip M. Overcoming the rising incidence and evolving mechanisms of antibiotic resistance by novel drug delivery approaches - An overview. Adv Drug Deliv Rev. 2022;181:114078. https://doi.org/10.1016/j.addr.2021.114078
Georgopapadakou NH, Smith SA, Bonner DP. Penicillin-binding proteins in a Staphylococcus aureus strain resistant to specific beta-lactam antibiotics. Antimicrob Agents Chemother. 1982;22(1):172-5. https://doi.org/10.1128/AAC.22.1.172
Cetinkaya Y, Falk P, Mayhall CG. Vancomycin-resistant enterococci. Clin Microbiol Rev. 2000; 13(4): 686-707. https://doi.org/10.1128/CMR.13.4.686
Gagetti P, Bonofiglio L, García Gabarrot G, Kaufman S, Mollerach M, Vigliarolo L, et al. Resistance to β-lactams in enterococci. Rev Argent Microbiol. 2019; 51(2):179-183. https://doi.org/10.1016/j.ram.2018.01.007
Gawryszewska I, Żabicka D, Hryniewicz W, Sadowy E. Penicillin-Resistant, Ampicillin-Susceptible Enterococcus faecalis in Polish Hospitals. Microb Drug Resist. 2021;27(3):291-300. https://doi.org/10.1089/mdr.2019.0504
Sakalauskienė GV, Malcienė L, Stankevičius E, Radzevičienė A. Unseen Enemy: Mechanisms of Multidrug Antimicrobial Resistance in Gram-Negative ESKAPE Pathogens. Antibiotics (Basel). 2025;14(1):63. https://doi.org/10.3390/antibiotics14010063
Glen KA, Lamont IL. Penicillin-binding protein 3 sequence variations reduce susceptibility of Pseudomonas aeruginosa to β-lactams but inhibit cell division. J Antimicrob Chemother. 2024;79(9):2170-2178. https://doi.org/10.1093/jac/dkae203
