Resisting Antibiotics through bacterial secretion of molecules that counteract antibiotic action

What is it about?

The overall antibiotic resistance of a bacterial population results from the combination of a wide range of susceptibilities displayed by subsets of bacterial cells. Bacterial heteroresistance to antibiotics has been documented for several opportunistic Gram-negative bacteria, but the mechanism of heteroresistance is unclear. We use Burkholderia cenocepacia as a model opportunistic bacterium to investigate the implications of heterogeneity in the response to the antimicrobial peptide polymyxin B (PmB) and also other bactericidal antibiotics. Here, we report that B. cenocepacia is heteroresistant to PmB. Population analysis profiling also identified B. cenocepacia subpopulations arising from a seemingly homogenous culture that are resistant to higher levels of polymyxin B than the rest of the cells in the culture, and can protect the more sensitive cells from killing, as well as sensitive bacteria from other species, such as Pseudomonas aeruginosa and Escherichia coli. Communication of resistance depended on upregulation of putrescine synthesis and YceI, a widely conserved low- molecular weight secreted protein. Deletion of genes for the synthesis of putrescine and YceI abrogate protection, while pharmacologic inhibition of putrescine synthesis reduced resistance to polymyxin B. Polyamines and YceI were also required for heteroresistance of B. cenocepacia to various bactericidal antibiotics. We propose that putrescine and YceI resemble "danger" infochemicals whose increased production by a bacterial subpopulation, becoming more resistant to bactericidal antibiotics, communicates higher level of resistance to more sensitive members of the population of the same or different species.

Featured Image

Why is it important?

Antibiotic resistance threatens the effectiveness of one of the foundations of modern medicine. Usually, the concern is about resistance that is inherent to the bacteria, or else develops in bacteria through genetic changes. Our research suggests another possibility, as we revealed that some species of bacteria may help others in surviving antibiotics. We identified a bacterial culture contains subpopulations that are more resistant to antibiotics than other bacteria of the same species. These resistant bacteria were more likely to survive antibiotic treatment and they can communicate resistance by releasing molecules that interfere with the action of the antibiotic, such as the polyamine putrescine and conserved lipocalin.