Monahan Leigh G, Turnbull Lynne, Osvath Sarah R, Birch Debra, Charles Ian G, Whitchurch Cynthia B
The ithree institute, University of Technology Sydney, Ultimo, NSW, Australia.
Antimicrob Agents Chemother. 2014;58(4):1956-62. doi: 10.1128/AAC.01901-13. Epub 2014 Jan 13.
The Gram-negative human pathogen Pseudomonas aeruginosa tolerates high concentrations of β-lactam antibiotics. Despite inhibiting the growth of the organism, these cell wall-targeting drugs exhibit remarkably little bactericidal activity. However, the mechanisms underlying β-lactam tolerance are currently unclear. Here, we show that P. aeruginosa undergoes a rapid en masse transition from normal rod-shaped cells to viable cell wall-defective spherical cells when treated with β-lactams from the widely used carbapenem and penicillin classes. When the antibiotic is removed, the entire population of spherical cells quickly converts back to the normal bacillary form. Our results demonstrate that these rapid population-wide cell morphotype transitions function as a strategy to survive antibiotic exposure. Taking advantage of these findings, we have developed a novel approach to efficiently kill P. aeruginosa by using carbapenem treatment to induce en masse transition to the spherical cell morphotype and then exploiting the relative fragility and sensitivity of these cells to killing by antimicrobial peptides (AMPs) that are relatively inactive against P. aeruginosa bacillary cells. This approach could broaden the repertoire of antimicrobial compounds used to treat P. aeruginosa and serve as a basis for developing new therapeutic agents to combat bacterial infections.
革兰氏阴性人类病原体铜绿假单胞菌能够耐受高浓度的β-内酰胺抗生素。尽管这些作用于细胞壁的药物会抑制该生物体的生长，但它们的杀菌活性却非常低。然而，目前尚不清楚β-内酰胺耐受性背后的机制。在此，我们表明，当用广泛使用的碳青霉烯类和青霉素类β-内酰胺类药物处理时，铜绿假单胞菌会迅速整体从正常的杆状细胞转变为有活力的细胞壁缺陷球形细胞。当去除抗生素后，整个球形细胞群体迅速恢复为正常的杆菌形态。我们的结果表明，这些快速的全群体细胞形态型转变是一种在抗生素暴露下存活的策略。利用这些发现，我们开发了一种新方法，通过使用碳青霉烯类药物诱导整体转变为球形细胞形态型，然后利用这些细胞相对脆弱且对原本对铜绿假单胞菌杆菌细胞相对无活性的抗菌肽（AMPs）杀伤敏感的特性，来有效杀死铜绿假单胞菌。这种方法可以拓宽用于治疗铜绿假单胞菌的抗菌化合物种类，并为开发对抗细菌感染的新治疗药物奠定基础。
