期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1863, 期 1, 页码 96-104出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2018.10.001
关键词
EBAs; Broad-spectrum antimicrobials; Membrane permeability; Mixed biofilms
资金
- Spanish Ministry of Economy, Industry and Competitiveness [BIO2013-47684-R, BIO2016-79323-R, SAF2017-88664-R]
- Spanish Instituto de Salud Carlos III [RETICS-FEDER RICET RD16/0027/0010]
- Spanish Instituto de Salud Carlos III (GIBER de Enfermedades Respiratorias - CIBERES)
Antibiotic resistance is a global current threat of increasing importance. Moreover, biofilms represent a medical challenge since the inherent antibiotic resistance of their producers demands the use of high doses of antibiotics over prolonged periods. Frequently, these therapeutic measures fail, contributing to bacterial persistence, therefore demanding the development of novel antimicrobials. Esters of bicyclic amines (EBAs), which are strong inhibitors of Streptococcus pneumoniae growth, were initially designed as inhibitors of pneumococcal choline-binding proteins on the basis of their structural analogy to the choline residues in the cell wall. However, instead of mimicking the characteristic cell chaining phenotype caused by exogenously added choline on planktonic cultures of pneumococcal cells, EBAs showed an unexpected lytic activity. In this work we demonstrate that EBAs display a second, and even more important, function as cell membrane destabilizers. We then assayed the inhibitory and disintegrating activity of these molecules on pneumococcal biofilms. The selected compound (EBA 31) produced the highest effect on S. pneumoniae (encapsulated and non-encapsulated) biofilms at very low concentrations. EBA 31 was also effective on mixed biofilms of non-encapsulated S. pneumoniae plus non typeable Haemophilus infiuenzae, two pathogens frequently forming a self-produced biofilm in the human nasopharynx. These results support the role of EBAs as a promising alternative for the development of novel, broad range antimicrobial drugs encompassing both Gram-positive and Gram-negative pathogens.
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