Beharry Zanna, Chen Hansong, Gadhachanda Venkat R, Buynak John D, Palzkill Timothy
Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Biochem Biophys Res Commun. 2004 Jan 16;313(3):541-5. doi: 10.1016/j.bbrc.2003.11.158.
Bacillus anthracis contains a class A (Bla1) and class B (Bla2) beta-lactamase, which confer resistance to beta-lactam antibiotics when expressed in Escherichia coli. In an effort to find new beta-lactamase inhibitors, several penicillin derivatives have been evaluated including experimental compounds incorporating a 6-mercaptomethyl group or a 6-pyridylmethylidene group, along with clavulanate and tazobactam, as inhibitors against Bla1 and Bla2. The 6-mercaptomethyl-substituted penicillins showed much greater activity against the zinc-containing Bla2 than Bla1. The compound that incorporated a 6-pyridylmethylidene substituent and a catecholic substituent at the 2' position was the most effective inhibitor of Bla1 with Ki=0.057 microM. Inhibitors containing iron-chelating functional groups have previously been shown to work in combination with antibiotics to inhibit growth of antibiotic-resistant bacteria expressing beta-lactamase. The development of similar compounds, incorporating these types of substituents, may help overcome resistance to currently used antibiotics.
炭疽芽孢杆菌含有A类（Bla1）和B类（Bla2）β-内酰胺酶，当它们在大肠杆菌中表达时可赋予对β-内酰胺抗生素的抗性。为了寻找新的β-内酰胺酶抑制剂，已对几种青霉素衍生物进行了评估，包括含有6-巯基甲基基团或6-吡啶基亚甲基基团的实验性化合物，以及克拉维酸和他唑巴坦，作为针对Bla1和Bla2的抑制剂。6-巯基甲基取代的青霉素对含锌的Bla2的活性比对Bla1的活性高得多。在2'位含有6-吡啶基亚甲基取代基和儿茶酚取代基的化合物是最有效的Bla1抑制剂，其Ki = 0.057 microM。先前已证明含有铁螯合官能团的抑制剂可与抗生素联合使用，以抑制表达β-内酰胺酶的耐抗生素细菌的生长。开发含有这些类型取代基的类似化合物可能有助于克服对目前使用的抗生素的耐药性。
