Panchal Rekha G, Ulrich Ricky L, Lane Douglas, Butler Michelle M, Houseweart Chad, Opperman Timothy, Williams John D, Peet Norton P, Moir Donald T, Nguyen Tam, Gussio Rick, Bowlin Terry, Bavari Sina
United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702-5011, USA.
Antimicrob Agents Chemother. 2009 Oct;53(10):4283-91. doi: 10.1128/AAC.01709-08. Epub 2009 Jul 27.
Given the limited number of structural classes of clinically available antimicrobial drugs, the discovery of antibacterials with novel chemical scaffolds is an important strategy in the development of effective therapeutics for both naturally occurring and engineered resistant strains of pathogenic bacteria. In this study, several diarylamidine derivatives were evaluated for their ability to protect macrophages from cell death following infection with Bacillus anthracis, a gram-positive spore-forming bacterium. Four bis-(imidazolinylindole) compounds were identified with potent antibacterial activity as measured by the protection of macrophages and by the inhibition of bacterial growth in vitro. These compounds were effective against a broad range of gram-positive and gram-negative bacterial species, including several antibiotic-resistant strains. Minor structural variations among the four compounds correlated with differences in their effects on bacterial macromolecular synthesis and mechanisms of resistance. In vivo studies revealed protection by two of the compounds of mice lethally infected with B. anthracis, Staphylococcus aureus, or Yersinia pestis. Taken together, these results indicate that the bis-(imidazolinylindole) compounds represent a new chemotype for the development of therapeutics for both gram-positive and gram-negative bacterial species as well as against antibiotic-resistant infections.
鉴于临床上可用的抗菌药物结构类型有限，发现具有新型化学骨架的抗菌药物是开发针对天然存在的和工程化耐药病原菌有效治疗方法的重要策略。在本研究中，评估了几种二芳基脒衍生物在巨噬细胞感染革兰氏阳性芽孢杆菌炭疽芽孢杆菌后保护其免于细胞死亡的能力。通过巨噬细胞保护和体外细菌生长抑制测定，鉴定出四种具有强效抗菌活性的双（咪唑啉吲哚）化合物。这些化合物对多种革兰氏阳性和革兰氏阴性细菌有效，包括几种抗生素耐药菌株。这四种化合物之间的微小结构差异与其对细菌大分子合成的影响和耐药机制的差异相关。体内研究表明，其中两种化合物可保护致死性感染炭疽芽孢杆菌、金黄色葡萄球菌或鼠疫耶尔森菌的小鼠。综上所述，这些结果表明双（咪唑啉吲哚）化合物代表了一种新的化学类型，可用于开发针对革兰氏阳性和革兰氏阴性细菌以及抗耐药感染的治疗药物。
