Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada.
Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
Appl Environ Microbiol. 2021 Apr 27;87(10). doi: 10.1128/AEM.00127-21.
The emergence and spread of extended-spectrum β-lactamases (ESBLs), metallo-β-lactamases (MBLs), or variant low-affinity penicillin-binding proteins (PBPs) pose a major threat to our ability to treat bacterial infection using β-lactam antibiotics. Although combinations of β-lactamase inhibitors with β-lactam agents have been clinically successful, there are no MBL inhibitors in current therapeutic use. Furthermore, recent clinical use of new-generation cephalosporins targeting PBP2a, an altered PBP, has led to the emergence of resistance to these antimicrobial agents. Previous work shows that natural polyphenols such as cranberry-extracted proanthocyanidins (cPAC) can potentiate non-β-lactam antibiotics against Gram-negative bacteria. This study extends beyond previous work by investigating the effect of cPAC in overcoming ESBL-, MBL-, and PBP2a-mediated β-lactam resistance. The results show that cPAC exhibit variable potentiation of different β-lactams against β-lactam-resistant clinical isolates as well as ESBL- and MBL-producing We also discovered that cPAC have broad-spectrum inhibitory properties on the activity of different classes of β-lactamases, including CTX-M3 ESBL and IMP-1 MBL. Furthermore, we observe that cPAC selectively potentiate oxacillin and carbenicillin against methicillin-resistant but not methicillin-sensitive staphylococci, suggesting that cPAC also interfere with PBP2a-mediated resistance. This study motivates the need for future work to identify the most bioactive compounds in cPAC and to evaluate their antibiotic-potentiating efficacy The emergence of β-lactam-resistant and staphylococci compromises the effectiveness of β-lactam-based therapy. By acquisition of ESBLs, MBLs, or PBPs, it is highly likely that bacteria may become completely resistant to the most effective β-lactam agents in the near future. In this study, we described a natural extract rich in proanthocyanidins which exerts adjuvant properties by interfering with two different resistance mechanisms. By their broad-spectrum inhibitory ability, cranberry-extracted proanthocyanidins could have the potential to enhance the effectiveness of existing β-lactam agents.
超广谱β-内酰胺酶（ESBLs）、金属β-内酰胺酶（MBLs）或变异低亲和力青霉素结合蛋白（PBPs）的出现和传播对我们使用β-内酰胺类抗生素治疗细菌感染的能力构成了重大威胁。虽然β-内酰胺酶抑制剂与β-内酰胺类药物的联合应用在临床上取得了成功，但目前尚无MBL 抑制剂在治疗中使用。此外，新型头孢菌素类药物针对改变的 PBP2a 的临床应用最近导致了这些抗菌药物的耐药性的出现。以前的工作表明，天然多酚如蔓越莓提取物原花青素（cPAC）可以增强针对革兰氏阴性菌的非β-内酰胺类抗生素的作用。本研究通过研究 cPAC 克服 ESBL、MBL 和 PBP2a 介导的β-内酰胺耐药的作用，扩展了以前的工作。结果表明，cPAC 对不同β-内酰胺类药物对β-内酰胺耐药的临床分离株以及产 ESBL 和 MBL 的菌株的作用具有不同的增效作用。我们还发现，cPAC 对不同类别的β-内酰胺酶的活性具有广谱抑制作用，包括 CTX-M3 ESBL 和 IMP-1 MBL。此外，我们观察到 cPAC 选择性增强了对耐甲氧西林但不敏感的金黄色葡萄球菌的苯唑西林和羧苄西林的作用，这表明 cPAC 还干扰了 PBP2a 介导的耐药性。本研究促使我们需要进一步确定 cPAC 中最具生物活性的化合物，并评估它们增强抗生素的功效。β-内酰胺类耐药菌和金黄色葡萄球菌的出现降低了基于β-内酰胺类的治疗的有效性。通过获得 ESBLs、MBLs 或 PBPs，细菌很可能在不久的将来对最有效的β-内酰胺类药物完全耐药。在本研究中，我们描述了一种富含原花青素的天然提取物，它通过干扰两种不同的耐药机制发挥辅助作用。蔓越莓提取物原花青素具有广谱抑制能力，有可能增强现有β-内酰胺类药物的有效性。
