Connelly Sheila, Fanelli Brian, Hasan Nur A, Colwell Rita R, Kaleko Michael
Synthetic Biologics, Inc., Rockville, MD 20850, USA.
CosmosID, Inc., Rockville, MD 20850, USA.
Microorganisms. 2020 Jan 22;8(2):152. doi: 10.3390/microorganisms8020152.
Beta-lactamases, enzymes produced by bacteria to degrade beta-lactam antibiotics, have been harnessed as therapeutics to protect the gut microbiome from damage caused by antibiotics. Proof-of-concept of this approach using SYN-004 (ribaxamase), a beta-lactamase formulated for oral delivery with intravenous (IV) penicillins and cephalosporins, was demonstrated with animal models and in humans. Ribaxamase degraded ceftriaxone in the gastrointestinal tract, protected the gut microbiome, significantly reduced the incidence of disease and attenuated emergence of antibiotic resistant organisms. SYN-007 is a delayed release formulation of ribaxamase intended for use with oral beta-lactams. In dogs treated with oral amoxicillin, SYN-007 diminished antibiotic-mediated microbiome disruption and reduced the emergence of antibiotic resistance without altering amoxicillin systemic absorption. Here, SYN-007 function in the presence of clavulanate, a beta-lactamase inhibitor, was investigated. Dogs received amoxicillin (40 mg/kg, orally (PO), three times a day (TID)) or the combined antibiotic/beta-lactamase inhibitor, amoxicillin/clavulanate (40 mg/kg amoxicillin, 5.7 mg/kg clavulanate, PO, TID) +/- SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were not significantly different +/- SYN-007 compared to amoxicillin alone or amoxicillin/clavulanate alone as controls for both first and last doses, indicating SYN-007 did not interfere with systemic absorption of the antibiotic. Whole genome shotgun metagenomics analyses of the fecal microbiomes demonstrated both amoxicillin and amoxicillin/clavulanate significantly reduced diversity and increased the frequency of antibiotic resistance genes. Microbiome damage appeared more severe with amoxicillin/clavulanate. In contrast, with SYN-007, microbiome diversity was not significantly altered, and frequency of antibiotic resistance genes did not increase. Importantly, SYN-007 functioned in the presence of clavulanate to protect the gut microbiome indicating that SYN-007 activity was not inhibited by clavulanate in the dog gastrointestinal tract. SYN-007 has the potential to expand microbiome protection to beta-lactam/beta-lactamase inhibitor combinations delivered orally or systemically.
β-内酰胺酶是细菌产生的用于降解β-内酰胺类抗生素的酶，已被用作治疗药物来保护肠道微生物群免受抗生素造成的损害。使用SYN-004（瑞巴派特酶）的这种方法的概念验证，即一种与静脉注射（IV）青霉素和头孢菌素一起口服给药的β-内酰胺酶，已在动物模型和人体中得到证实。瑞巴派特酶在胃肠道中降解头孢曲松，保护肠道微生物群，显著降低疾病发生率，并减少抗生素耐药菌的出现。SYN-007是一种瑞巴派特酶的缓释制剂，旨在与口服β-内酰胺类药物联合使用。在用口服阿莫西林治疗的犬中，SYN-007减少了抗生素介导的微生物群破坏，并减少了抗生素耐药性的出现，而不改变阿莫西林的全身吸收。在此，研究了SYN-007在β-内酰胺酶抑制剂克拉维酸盐存在下的功能。犬接受阿莫西林（40mg/kg，口服（PO），每日三次（TID））或联合抗生素/β-内酰胺酶抑制剂阿莫西林/克拉维酸盐（40mg/kg阿莫西林，5.7mg/kg克拉维酸盐，PO，TID）+/-SYN-007（10mg，PO，TID），持续五天。与单独使用阿莫西林或单独使用阿莫西林/克拉维酸盐作为首剂和末次剂量的对照相比，+/-SYN-007时血清阿莫西林水平无显著差异，表明SYN-007不干扰抗生素的全身吸收。对粪便微生物群的全基因组鸟枪法宏基因组学分析表明，阿莫西林和阿莫西林/克拉维酸盐均显著降低了多样性，并增加了抗生素耐药基因的频率。阿莫西林/克拉维酸盐导致的微生物群损伤似乎更严重。相比之下，使用SYN-007时，微生物群多样性没有显著改变，抗生素耐药基因的频率也没有增加。重要的是，SYN-007在克拉维酸盐存在下发挥作用以保护肠道微生物群，表明SYN-007的活性在犬胃肠道中未被克拉维酸盐抑制。SYN-007有可能将微生物群保护扩展到口服或全身给药的β-内酰胺/β-内酰胺酶抑制剂组合。
