Edowik Yasir, Caspari Thomas, Williams Hugh Merfyn
School of Medical Sciences, Bangor University, Brigantia Building, Penrallt Road, Bangor, Gwynedd, Wales LL57 2AS, UK.
Faculty of Medicine, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria.
Microorganisms. 2020 Dec 13;8(12):1983. doi: 10.3390/microorganisms8121983.
The antibiotic nitrofurantoin is a furan flanked by a nitro group and a hydantoin ring. It is used to treat lower urinary tract infections (UTIs) that have a lifetime incidence of 50-60% in adult women. UTIs are typically caused by uropathogenic (UPEC), which are increasingly expressing extended-spectrum beta-lactamases (ESBL), rendering them multi-drug resistant. Nitrofurantoin is a first-line treatment for gram-negative ESBL-positive UTI patients, given that resistance to it is still rare (0% to 4.4%). Multiplex PCR of β-lactamase genes of the groups 1, 2, 9 and 8/25 from ESBL-positive UTI patients treated at three referral hospitals in North Wales (UK) revealed the presence of a novel gene harbouring the missense mutations T55A, A273P and R277C. While R277 is close to the active site, T55 and A273 are both located in external loops. Recombinant expression of CTX-M-14 and the mutated CTX-M-14 in the periplasm of revealed a significant increase in the Minimum Inhibitory Concentration (MIC) for nitrofurantoin from ≥6 μg/mL (CTX-M-14) to ≥512 μg/mL (mutated CTX-M-14). Consistent with this finding, the mutated CTX-M protein hydrolysed nitrofurantoin in a cell-free assay. Detection of a novel nitrofurantoin resistance gene indicates an emerging clinical problem in the treatment of gram-negative ESBL-positive UTI patients.
抗生素呋喃妥因是一个呋喃环两侧分别连接一个硝基和一个乙内酰脲环。它用于治疗下尿路感染（UTIs），成年女性一生中患下尿路感染的几率为50%-60%。尿路感染通常由尿路致病性大肠杆菌（UPEC）引起，这些细菌越来越多地表达超广谱β-内酰胺酶（ESBL），使其具有多重耐药性。呋喃妥因是革兰氏阴性ESBL阳性尿路感染患者的一线治疗药物，因为对其产生耐药性的情况仍然很少见（0%至4.4%）。对在英国北威尔士三家转诊医院接受治疗的ESBL阳性尿路感染患者的1、2、9和8/25组β-内酰胺酶基因进行多重PCR检测，发现存在一个携带错义突变T55A、A273P和R277C的新基因。虽然R277靠近活性位点，但T55和A273都位于外环。CTX-M-14和突变的CTX-M-14在周质中的重组表达显示，呋喃妥因的最低抑菌浓度（MIC）从≥6μg/mL（CTX-M-14）显著增加到≥512μg/mL（突变的CTX-M-14）。与这一发现一致，在无细胞试验中，突变的CTX-M蛋白水解了呋喃妥因。检测到一种新的呋喃妥因耐药基因表明，在治疗革兰氏阴性ESBL阳性尿路感染患者方面出现了一个新的临床问题。
