Razi Journal of Medical Sciences

fa مروری بر مکانیسم‌های اثر و مقاومت در آنتی‌بیوتیک‌های جدید مبتنی بر بتالاکتام ها A Review of the Mechanisms of Action and Resistance in New Beta-Lactam-Based Antibiotics میکروبیولوژی Microbiology مروري review article <div style="text-align: justify;">مقاومت میکروبی یکی از مهم‌ترین چالش‌های بهداشتی جهانی در قرن 21 محسوب می‌شود. مدیریت عفونت‌های ناشی از باکتری‌های گرم منفی مقاوم به چند دارو دشوار بوده و تهدیدی جدی برای سلامت عمومی محسوب می‌شود که به‌طور قابل‌توجهی به افزایش میزان بیماری و مرگ‌ومیر کمک می‌کند. مکانیسم‌های اصلی مقاومت در این باکتری‌ها شامل کاهش نفوذ دارو، تغییر در اهداف دارویی، غیرفعال‌سازی دارو و خروج فعال آن از طریق پمپ‌های افلاکس است. با توجه به تکامل سریع مقاومت، درمان‌های ترکیبی به‌عنوان راهبردهای بالقوه برای غلبه بر مقاومت دارویی و بهبود اثربخشی درمان مورد توجه قرار گرفته‌اند. آنتی‌بیوتیک‌های ترکیبی عملکرد مناسبی در برابر باکتری‌های مقاوم نشان داده‌اند. با این حال، ظهور سویه‌های مقاوم به این ترکیبات زنگ خطری برای مصرف بهینه آنتی‌بیوتیک‌ها محسوب می‌شود. جهش‌ در ژن‌های مرتبط با پمپ‌های افلاکس و تنظیم‌کننده‌های آن‌ها و همچنین در پروتئین‌های متصل‌شونده به دارو و پورین‌ها می‌تواند موجب بروز مقاومت به این داروها شود. مطالعات بسیاری درباره آنتی‌بیوتیک‌های جدید که باکتری‌های مقاوم را هدف قرار می‌دهند انجام شده است. اما تحقیقات جامع درباره مکانیسم‌های اثر، طیف اثرگذاری و مقاومت در برابر آن ها محدود است. درک مشکل مقاومت در برابر آنتی‌بیوتیک‌های جدید و اجرای اقدامات پیشگیرانه برای جلوگیری از گسترش این مقاومت امری حیاتی است. این مرور علمی به بررسی مکانیسم‌های عملکرد و پروفایل‌های مقاومتی آنتی‌بیوتیک‌های جدیدی می‌پردازد که برای مقابله با عفونت‌های ناشی از پاتوژن‌های گرم منفی مقاوم به کارباپنم و مقاوم به چند دارو طراحی شده‌اند. آنتی‌بیوتیک‌های مورد بحث شامل سفپیم-زیدباکتام، سفپیم-تانیبورباکتام، سفتازیدیم-آویباکتام، ایمی‌پنم-رلباکتام، سفیدروکل، سفتولوزان-تازوباکتام، مروپنم-وابورباکتام و آزترئونام-آویباکتام هستند.</div> <div style="text-align: justify;"> Antibiotic resistance has emerged as one of the major global health challenges of the 21st century, resulting in increased morbidity and mortality. The World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) have recognized antimicrobial resistance as a significant threat to public health. In particular, multidrug-resistant (MDR) Gram-negative bacteria play a crucial role in nosocomial infections. This study focuses on investigating new antibiotics and drug combinations that are effective against MDR Gram-negative bacteria. The aim of this research is to provide comprehensive insights into novel drugs and β-lactamase inhibitory compounds in the fight against antibiotic resistance, ultimately helping to improve therapeutic strategies. This review demonstrates that novel antibiotics, such as cefepime/Taniborbactam, ceftazidime/avibactam, cefiderocol, cefepime/zidebactam, imipenem/relebactam, ceftolozane/tazobactam, meropenem/vaborbactam, and aztreonam/avibactam, offer promising alternatives for addressing infections caused by carbapenem-resistant and multidrug-resistant Gram-negative bacteria. Nonetheless, a significant obstacle in the practical utilization of these antibiotics is the swift development of resistance to them. Mechanisms of resistance in Gram-negative bacteria include reduced drug penetration, modification of the drug target, drug inactivation, and drug efflux through efflux pumps. Each of these antibiotics demonstrated varying degrees of effectiveness against drug-resistant bacteria. The results for each compound are summarized as follows: Cefepime/zidebactam is a combination of a fourth-generation cephalosporin and a β-lactamase inhibitor that targets a broad spectrum of resistant bacteria, particularly carbapenem-resistant Enterobacteriaceae and MDR/extensively drug-resistant (XDR) P. aeruginosa. In addition to inhibiting β-lactamases, zidebactam enhances bactericidal effect by binding to penicillin-binding protein 2 (PBP2), while cefepime inhibits PBP3, distinguishing this combination from other β-lactamase inhibitors. Resistance to this compound seems to arise from multiple mutations in the genes encoding the MexAB-OprM efflux pump and its regulators, as well as in PBP2 and PBP3. Taniborbactam, a boronic acid β-lactamase inhibitor, has been studied in combination with cefepime against carbapenem-resistant bacteria. This combination is effective against class A, C, and D β-lactamases, as well as some class B metallo-β-lactamases. In vitro studies have demonstrated that cefepime-taniborbactam exhibits a broad spectrum of antibacterial activity and is effective against strains resistant to other β-lactamase inhibitors. Alterations in electrostatic charges within the active-site loops of metallo-β-lactamases, due to single amino acid substitutions, can reduce the binding affinity of taniborbactam. Ceftolozane-tazobactam is an anti-pseudomonal cephalosporin approved for the treatment of complicated urinary tract infections (cUTI) and complicated intra-abdominal infection (cIAI). This combination is effective against carbapenem-resistant P. aeruginosa and some Enterobacteriaceae, but it has limited activity against Acinetobacter baumannii and some other Enterobacteriaceae. Resistance to this combination is typically associated with increased AmpC expression, mutations in PBP3, and enhanced efflux pump activity. Ceftolozane-tazobactam may show reduced efficacy against isolates harboring co-produced class A and D β-lactamases, carbapenemases, and metallo-β-lactamases. Ceftazidime-avibactam is a combination of a third-generation cephalosporin and a β-lactamase inhibitor, effective against carbapenem-resistant bacteria and Pseudomonas aeruginosa. Ceftazidime-avibactam shown effectiveness in managing bloodstream infections due to carbapenem-resistant Enterobacteriaceae; nevertheless, its clinical outcomes may vary in instances of pneumonia or deep-seated infections. This heterogeneity is likely due to disparities in medication penetration and bacterial load at the infection site. Resistance to ceftazidime-avibactam in Enterobacteriaceae is predominantly associated with three principal mechanisms: enzymatic modifications that inactivate the antibiotic, modifications of the drug target, and diminished cell permeability or enhanced efflux pump function. The combination of meropenem with vaborbactam is effective against KPC-producing Enterobacteriaceae and was approved by the Food and Drug Administration (FDA) in 2017 for the treatment of cUTI. This combination is particularly effective against carbapenem-resistant bacteria, although its activity against OXA- and metallo-β-lactamase-producing isolates is limited. It is capable of penetrating the outer membrane of Klebsiella pneumoniae via the OmpK35 and OmpK36 porins. Resistance to this combination is typically linked to reduced membrane permeability and mutations in the OmpK35 and OmpK36 porins, along with increased expression of the blaKPC gene. Imipenem-relebactam is utilized for the management of complex infections. Relebactam serves as a powerful inhibitor of class A and C β-lactamases, hence augmenting the effectiveness of imipenem against resistant bacteria. Resistance to imipenem-relebactam may develop by multiple mechanisms, such as the overproduction of oxacillinases, metallo-β-lactamases, or other β-lactamases, enhanced efflux pumps activity, diminished membrane permeability, and mutations in the OmpK36 and OmpK35 porins. Cefiderocol is a novel antibiotic approved for cUTI and ventilator-associated pneumonia (VAP). It demonstrates high efficacy against MDR bacteria. It is transported into bacterial cells through iron uptake systems, where it inhibits PBPs and subsequently disrupts bacterial cell wall synthesis. Although it remains stable against β-lactamases, resistance may develop due to mutations in siderophore receptors and PBP-3. The combination of aztreonam and avibactam has been demonstrated to enhance the antimicrobial activity of aztreonam and restore its efficacy against MDR bacteria. This combination inhibited 99.9% of Enterobacteriaceae at concentrations of ≤ 8 mg/L. However, resistance may develop through the production of extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases, as well as mutations in PBP3 or through the action of efflux pumps. This review demonstrates that although new antibiotics are initially highly effective, resistance to them develops rapidly. This phenomenon limits their clinical use and reduces treatment options, ultimately accelerating the spread of resistant strains. Therefore, effective management and rational use of antibiotics are essential to prevent the spread of resistance and maintain the efficacy of existing treatments. Adhering to the principles of rational antibiotic use, developing alternative compounds and rapid diagnostic tools, and conducting further research in areas with a high prevalence of resistant infections can significantly contribute to reducing resistance rates and enhancing antimicrobial therapies. </div> مقاومت ضد میکروبی, باکتری‌های مقاوم به چند دارو, آنتی بیوتیک‌های جدید, بتالاکتام-مهارکننده بتالاکتاماز, مقاومت به کارباپنم ‌ Antimicrobial resistance, Multidrug-resistant (MDR) bacteria, Carbapenem-resistant, Novel antibiotics, β-lactam/β-lactamase inhibitors 1 36 http://rjms.iums.ac.ir/browse.php?a_code=A-10-4870-2&slc_lang=fa&sid=1 Milad Kashi میلاد کاشی 3900319475328460088978 0009-0005-0890-0817 No Student research committee, Arak University of Medical Sciences, Arak, Iran کمیته تحقیقات دانشجویی، دانشگاه علوم پزشکی اراک، اراک، ایران Yasaman Hariri یاسمن حریری 3900319475328460088979 0009-0008-7315-5819 No Student research committee, Arak University of Medical Sciences, Arak, Iran کمیته تحقیقات دانشجویی، دانشگاه علوم پزشکی اراک، اراک، ایران Seyede Vania Amiri سیده وانیا امیری 3900319475328460088980 0009-0009-7335-0216 No Student research committee, Arak University of Medical Sciences, Arak, Iran کمیته تحقیقات دانشجویی، دانشگاه علوم پزشکی اراک، اراک، ایران Atefeh Mosayebi Dashtaki عاطفه مسیبی دشتکی 3900319475328460088981 0009-0002-4354-8597 No Student research committee, Arak University of Medical Sciences, Arak, Iran کمیته تحقیقات دانشجویی، دانشگاه علوم پزشکی اراک، اراک، ایران Yasaman Shariati یاسمن شریعتی 3900319475328460088982 0009-0004-6141-2428 No Student research committee, Arak University of Medical Sciences, Arak, Iran کمیته تحقیقات دانشجویی، دانشگاه علوم پزشکی اراک، اراک، ایران Aref Shariati عارف شریعتی arefshariati0111@gmail.com 3900319475328460088983 3900319475328460088983 Yes Infectious Diseases Research Center (IDRC), Arak University of Medical Sciences, Arak, Iran مرکز تحقیقات بیماری‌های عفونی، دانشگاه علوم پزشکی اراک، اراک، ایران