Abstract
In nature, most bacteria live in biofilms where they compete with their siblings and other species for space and nutrients. Some bacteria produce antibiotics in biofilms; however, since the diffusion of antibiotics is generally hindered in biofilms by extracellular polymeric substances, i.e., the biofilm matrix, their function remains unclear. The Bacillus subtilis yitPOM operon is a paralog of the sdpABC operon, which produces the secreted peptide toxin SDP. Unlike sdpABC, yitPOM is induced in biofilms by the DegS-DegU two-component regulatory system. High yitPOM expression leads to the production of a secreted toxin called YIT. Expression of yitQ, which lies upstream of yitPOM, confers resistance to the YIT toxin, suggesting that YitQ is an anti-toxin protein for the YIT toxin. The alternative sigma factor SigW also contributes to YIT toxin resistance. In a mutant lacking yitQ and sigW, the YIT toxin specifically inhibits biofilm formation, and the extracellular neutral protease NprB is required for this inhibition. The requirement for NprB is eliminated by Δeps and ΔbslA mutations, either of which impairs production of biofilm matrix polymers. Overexpression of biofilm matrix polymers prevents the action of the SDP toxin but not the YIT toxin. These results indicate that, unlike the SDP toxin and many conventional antibiotics, the YIT toxin can pass through layers of biofilm matrix polymers to attack cells within biofilms with assistance from NprB. When the wild-type strain and the YIT-sensitive mutant were grown together on a solid medium, the wild-type strain formed biofilms that excluded the YIT-sensitive mutant. This observation suggests that the YIT toxin protects B. subtilis biofilms against competitors. Several bacteria are known to produce antibiotics in biofilms. We propose that some bacteria including B. subtilis may have evolved specialized antibiotics that can function within biofilms.
Highlights
IntroductionBacteria compete for space and nutrients [1]. Antibiotics are thought to play a critical role in this competition, and antibiotic-producing bacteria are common in various environments [2,3,4]
In the environment, bacteria compete for space and nutrients [1]
We demonstrated that B. subtilis produces a secreted peptide antibiotic called the YIT toxin and its resistant proteins in biofilms
Summary
Bacteria compete for space and nutrients [1]. Antibiotics are thought to play a critical role in this competition, and antibiotic-producing bacteria are common in various environments [2,3,4]. In the environment, most bacteria are found in sessile multicellular bacterial communities known as biofilms, in which bacteria exhibit increased antibiotic tolerance or resistance [5, 6]. When encased in the biofilm matrix, cells exhibit increased tolerance or resistance to environmental stresses, antibiotics, host defense systems, and predation [8, 9]. Since the properties of biofilms, including the protection of member cells by the biofilm matrix, the increased expression of antibiotic resistance genes, and the decreased internal fluidity, reduce the efficacy of antibiotics against biofilm cells [11,12,13,14,15,16], little attention has been paid to the functions of antibiotics in competition within biofilms. An understanding of how bacteria use antibiotics in biofilms will provide insight into bacterial survival strategies within biofilms, it will lead to the discovery of tactics for combating biofilm-related problems, such as food and beverage safety issues, industrial contamination, and biofilm-related diseases
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