Microbial biofilms are involved in a number of infections that cannot be cured, as microbes in biofilms resist host immune defenses and antibiotic therapies. With no strict biofilm-antibiotic in the current pipelines, there is an unmet need for drug candidates that enable the current antibiotics to eradicate bacteria in biofilms. We used high-throughput screening to identify chemical compounds that reduce the intracellular c-di-GMP content in Pseudomonas aeruginosa. This led to the identification of a small molecule that efficiently depletes P. aeruginosa for c-di-GMP, inhibits biofilm formation, and disperses established biofilm. A combination of our lead compound with standard of care antibiotics showed improved eradication of an implant-associated infection established in mice. Genetic analyses provided evidence that the anti-biofilm compound stimulates the activity of the c-di-GMP phosphodiesterase BifA in P. aeruginosa. Our work constitutes a proof of concept for c-di-GMP phosphodiesterase-activating drugs administered in combination with antibiotics as a viable treatment strategy for otherwise recalcitrant infections.

微生物生物膜涉及许多无法治愈的感染，因为生物膜中的微生物抵抗宿主免疫防御和抗生素疗法。由于目前的管道中没有严格的生物膜抗生素，因此对使当前抗生素能够根除生物膜中细菌的候选药物的需求未得到满足。我们使用高通量筛选来鉴定降低铜绿假单胞菌细胞内 c-di-GMP 含量的化合物。这导致鉴定了一种有效消耗铜绿假单胞菌的小分子对于 c-di-GMP，抑制生物膜形成，并分散已建立的生物膜。我们的先导化合物与标准护理抗生素的组合显示出更好地根除小鼠体内植入物相关感染的效果。遗传分析提供的证据表明，抗生物膜化合物可刺激铜绿假单胞菌中c-di-GMP 磷酸二酯酶 BifA 的活性。我们的工作证明了 c-di-GMP 磷酸二酯酶激活药物与抗生素联合使用作为治疗顽固感染的可行治疗策略的概念证明。