Nishida K, Kunugita C, Uji T, Higashitani F, Hyodo A, Unemi N, Maiti S N, Phillips O A, Spevak P, Atchison K P, Salama S M, Atwal H, Micetich R G
Antimicrobial Research Laboratory, Taiho Pharmaceutical Co., Ltd. Tokushima 771-0194, Japan.
Antimicrob Agents Chemother. 1999 Aug;43(8):1895-900. doi: 10.1128/AAC.43.8.1895.
Syn2190, a monobactam derivative containing 1,5-dihydroxy-4-pyridone as the C-3 side chain, is a potent inhibitor of group 1 beta-lactamase. The concentrations of inhibitor needed to reduce the initial rate of hydrolysis of substrate by 50% for Syn2190 against these enzymes were in the range of 0.002 to 0.01 microM. These values were 220- to 850-fold lower than those of tazobactam. Syn2190 showed in vitro synergy with ceftazidime and cefpirome. This synergy was dependent on the concentration of the inhibitor against group 1 beta-lactamase-producing strains, such as Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, and Morganella morganii. However, against beta-lactamase-derepressed mutants of P. aeruginosa, the MICs of ceftazidime plus Syn2190 were not affected by the amount of beta-lactamase, and the values were the same for the parent strains. The MICs at which 50% of isolates are inhibited (MIC(50)s) of ceftazidime plus Syn2190 were 2- to 16-fold lower than those of ceftazidime alone for ceftazidime-resistant, clinically isolated gram-negative bacteria. Similarly, the MIC(50)s of cefpirome plus Syn2190 were two- to eightfold lower for cefpirome-resistant clinical isolates. The synergies of Syn2190 plus ceftazidime or cefpirome observed in vitro were also reflected in vivo. Syn2190 improved the efficacies of both cephalosporins in both a murine systemic infection model with cephalosporin-resistant rods and urinary tract infection models with cephalosporin-resistant P. aeruginosa.
Syn2190是一种含有1,5 - 二羟基 - 4 - 吡啶酮作为C - 3侧链的单环β - 内酰胺衍生物，是1类β - 内酰胺酶的强效抑制剂。对于这些酶，Syn2190将底物水解初始速率降低50%所需的抑制剂浓度在0.002至0.01微摩尔范围内。这些值比他唑巴坦低220至850倍。Syn2190在体外与头孢他啶和头孢匹罗表现出协同作用。这种协同作用取决于抑制剂对产生1类β - 内酰胺酶的菌株的浓度，如铜绿假单胞菌、阴沟肠杆菌、弗氏柠檬酸杆菌和摩根摩根菌。然而，对于铜绿假单胞菌的β - 内酰胺酶去阻遏突变体，头孢他啶加Syn2190的最低抑菌浓度不受β - 内酰胺酶量的影响，其值与亲本菌株相同。对于耐头孢他啶的临床分离革兰氏阴性菌，头孢他啶加Syn2190使50%分离株被抑制时的最低抑菌浓度（MIC50）比单独使用头孢他啶低2至16倍。同样，对于耐头孢匹罗的临床分离株，头孢匹罗加Syn2190的MIC50低2至8倍。在体外观察到的Syn2190加头孢他啶或头孢匹罗的协同作用在体内也有体现。在耐头孢菌素的杆菌的小鼠全身感染模型和耐头孢他啶的铜绿假单胞菌的尿路感染模型中，Syn2190均提高了两种头孢菌素的疗效。
