Research in Molecular Medicine

en Narrative Review of β-Lactam Resistance in Key Bacterial Pathogens: Efficacy and Innovations in Combination Therapies باکتری شناسی پزشکی Medical bacteriology review review <div style="text-align: justify;">Background: β-Lactam antibiotics (BLIs) are essential for treating bacterial infections, but resistance is increasing due to β-lactamases, altered penicillin-binding proteins (PBPs), and reduced permeability in pathogens, such as E. coli, K. pneumoniae, P. aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), A. baumannii, N. gonorrhoeae, and vancomycin-resistant Enterococcus faecium. BLIs aim to restore the effectiveness of these antibiotics, but non-enzymatic resistance remains a challenge. Methods: This narrative review searched databases including PubMed, Scopus, Web of Science, and Google Scholar for articles published between 2020 and 2025. Key search terms included "beta-lactam resistance" and "clustered regularly interspaced short palindromic repeats (CRISPR)-mediated antimicrobial resistance." Out of approximately 1,200 articles, 88 peer-reviewed studies were selected, focusing on resistance mechanisms, prevalence, and innovative therapies for selected pathogens. Results: E. coli and K. pneumoniae exhibit high prevalence rates of extended-spectrum β-lactamases, with Cefotaximase‑Munich (CTX-M) found in 72.5% of cases and carbapenemase blaKPC-2 in 66% of K. pneumoniae. Methicillin-resistant Staphylococcus aureus (MRSA) relies on the mecA gene (30% prevalence in burn infections), while A. baumannii shows a prevalence of blaOXA-23 at 68.9%, and N. gonorrhoeae has blaTEM-1 in 86.88% of cases. The combination of ceftazidime and avibactam reduces mortality in carbapenem-resistant K. pneumoniae (CRKP) infections by 52%, with additional synergy observed when combined with aztreonam (89% effectiveness). Phage therapy and CRISPR/Cas9 have shown effectiveness in targeting multidrug-resistant (MDR) strains and restoring susceptibility. Conclusion: Managing β-lactam resistance effectively requires a deep understanding of pathogen-specific mechanisms. While β-lactamase inhibitors (BLIs), such as ceftazidime/avibactam, are useful, their effectiveness is limited by efflux pumps and modifications to penicillin-binding proteins (PBPs). Bacteriophage therapy has proven highly effective in significantly reducing multidrug-resistant (MDR) A. baumannii in vivo, and CRISPR/Cas9 can precisely target resistance genes such as blaKPC to restore antibiotic sensitivity. Additionally, nanocarrier systems improve drug delivery by overcoming challenges like efflux and biofilm formation. This review synthesizes advancements made since 2020, highlighting innovative strategies involving phage therapy, CRISPR, and nanocarriers, while addressing critical research gaps in understudied pathogens, paving the way for precision antimicrobial therapies. Background: β-Lactam antibiotics (BLIs) are essential for treating bacterial infections, but resistance is increasing due to β-lactamases, altered penicillin-binding proteins (PBPs), and reduced permeability in pathogens, such as E. coli, K. pneumoniae, P. aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), A. baumannii, N. gonorrhoeae, and vancomycin-resistant Enterococcus faecium. BLIs aim to restore the effectiveness of these antibiotics, but non-enzymatic resistance remains a challenge. Methods: This narrative review searched databases including PubMed, Scopus, Web of Science, and Google Scholar for articles published between 2020 and 2025. Key search terms included "beta-lactam resistance" and "clustered regularly interspaced short palindromic repeats (CRISPR)-mediated antimicrobial resistance." Out of approximately 1,200 articles, 88 peer-reviewed studies were selected, focusing on resistance mechanisms, prevalence, and innovative therapies for selected pathogens. Results: E. coli and K. pneumoniae exhibit high prevalence rates of extended-spectrum β-lactamases, with Cefotaximase‑Munich (CTX-M) found in 72.5% of cases and carbapenemase blaKPC-2 in 66% of K. pneumoniae. Methicillin-resistant Staphylococcus aureus (MRSA) relies on the mecA gene (30% prevalence in burn infections), while A. baumannii shows a prevalence of blaOXA-23 at 68.9%, and N. gonorrhoeae has blaTEM-1 in 86.88% of cases. The combination of ceftazidime and avibactam reduces mortality in carbapenem-resistant K. pneumoniae (CRKP) infections by 52%, with additional synergy observed when combined with aztreonam (89% effectiveness). Phage therapy and CRISPR/Cas9 have shown effectiveness in targeting multidrug-resistant (MDR) strains and restoring susceptibility. Conclusion: Managing β-lactam resistance effectively requires a deep understanding of pathogen-specific mechanisms. While β-lactamase inhibitors (BLIs), such as ceftazidime/avibactam, are useful, their effectiveness is limited by efflux pumps and modifications to penicillin-binding proteins (PBPs). Bacteriophage therapy has proven highly effective in significantly reducing multidrug-resistant (MDR) A. baumannii in vivo, and CRISPR/Cas9 can precisely target resistance genes such as blaKPC to restore antibiotic sensitivity. Additionally, nanocarrier systems improve drug delivery by overcoming challenges like efflux and biofilm formation. This review synthesizes advancements made since 2020, highlighting innovative strategies involving phage therapy, CRISPR, and nanocarriers, while addressing critical research gaps in understudied pathogens, paving the way for precision antimicrobial therapies.</div> Beta-Lactam, Klebsiella pneumonia, CRISPR/Cas9, β-Lactamase inhibitors 0 0 http://rmm.mazums.ac.ir/browse.php?a_code=A-10-1365-4&slc_lang=en&sid=1 Rouzbeh Sojoudi Masuleh rouzbehs77@gmail.com 100319475328460013498 100319475328460013498 No Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Zahra Salimian Rizi zahra.salimian2001@gmail.com 100319475328460013499 100319475328460013499 No Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran Ali Rashidi iamalirashidi2020@gmail.com 100319475328460013500 100319475328460013500 No Department of Microbiology, Razi Vaccine and Serum Research Institute, Karaj, Iran Amir Hossein Salek Khalili amirhsk81@gmail.com 100319475328460013501 100319475328460013501 No Department of Medical Bacteriology, School of Medicine, Shahed University, Tehran, Iran. Seyedeh Zahra Mohsenzadeh Mohsenzademahyaa@gmail.com 100319475328460013502 100319475328460013502 No Medical Laboratory Science, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. Ghazale Aghaei Ghazaleh.aghaee8080@gmail.com 100319475328460013503 100319475328460013503 No Department of Microbiology, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran. Mohammad Karimbakhsh mohammadkarimbakhsh1@gmail.com 100319475328460013504 100319475328460013504 Yes Department of Bacteriology, Pasteur institute of Iran, Tehran, Iran.