Abstract
ABSTRACTIn natural environments, antibiotics are important means of interspecies competition. At subinhibitory concentrations, they act as cues or signals inducing antibiotic production; however, our knowledge of well-documented antibiotic-based sensing systems is limited. Here, for the soil actinobacterium Streptomyces lincolnensis, we describe a fundamentally new ribosome-mediated signaling cascade that accelerates the onset of lincomycin production in response to an external ribosome-targeting antibiotic to synchronize antibiotic production within the population. The entire cascade is encoded in the lincomycin biosynthetic gene cluster (BGC) and consists of three lincomycin resistance proteins in addition to the transcriptional regulator LmbU: a lincomycin transporter (LmrA), a 23S rRNA methyltransferase (LmrB), both of which confer high resistance, and an ATP-binding cassette family F (ABCF) ATPase, LmrC, which confers only moderate resistance but is essential for antibiotic-induced signal transduction. Specifically, antibiotic sensing occurs via ribosome-mediated attenuation, which activates LmrC production in response to lincosamide, streptogramin A, or pleuromutilin antibiotics. Then, ATPase activity of the ribosome-associated LmrC triggers the transcription of lmbU and consequently the expression of lincomycin BGC. Finally, the production of LmrC is downregulated by LmrA and LmrB, which reduces the amount of ribosome-bound antibiotic and thus fine-tunes the cascade. We propose that analogous ABCF-mediated signaling systems are relatively common because many ribosome-targeting antibiotic BGCs encode an ABCF protein accompanied by additional resistance protein(s) and transcriptional regulators. Moreover, we revealed that three of the eight coproduced ABCF proteins of S. lincolnensis are clindamycin responsive, suggesting that the ABCF-mediated antibiotic signaling may be a widely utilized tool for chemical communication.
Highlights
IMPORTANCE Resistance proteins are perceived as mechanisms protecting bacteria from the inhibitory effect of their produced antibiotics or antibiotics from competitors
In contrast and more importantly, we revealed that the LmrC ATP-binding cassette family F (ABCF) ATPase is dispensable for self-protection, but it is a key component of an antibiotic-induced cascade, which directs the onset of lincomycin biosynthesis through a transcriptional regulator, LmbU [24, 25], and in cooperation with lincomycin transporter (LmrA) and LmrB resistance proteins
We knocked out lmrA, lmrB, and lmrC singly or in pairs in the lincomycin-producing S. lincolnensis wild-type (WT) strain (Fig. 1b) and, in addition, we complemented the genes under the mbio.asm.org 3 control of a constitutive or natural promoter acting in trans
Summary
IMPORTANCE Resistance proteins are perceived as mechanisms protecting bacteria from the inhibitory effect of their produced antibiotics or antibiotics from competitors. The current concept is that antibiotics are produced as a response to cues from competitors to defend the habitats of the organism, producing them in natural competitive environments [2,3,4,5] These cues involve ribosome-targeting antibiotics, which at subinhibitory concentrations act as elicitors of secondary metabolism [6,7,8]. Apart from truly biosynthetic genes, BGCs of 50S ribosomal subunit-targeting antibiotics encode regulation elements for timely and coordinated production and resistance mechanisms for self-protection. In contrast and more importantly, we revealed that the LmrC ABCF ATPase is dispensable for self-protection, but it is a key component of an antibiotic-induced cascade, which directs the onset of lincomycin biosynthesis through a transcriptional regulator, LmbU [24, 25], and in cooperation with LmrA and LmrB resistance proteins. The dual resistance-regulatory function of the LmrC ABCF protein reported here is unprecedented
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
