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Review
. 2011 Sep 14;111(9):5492-505.
doi: 10.1021/cr2000509. Epub 2011 Jul 25.

Antibiotics as signal molecules

Diego Romero  1 , Matthew F Traxler, Daniel López, Roberto Kolter
Affiliations
Review

Antibiotics as signal molecules

Diego Romero et al. Chem Rev. .
No abstract available

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Figures

Figure 1
Figure 1
Quorum sensing communication systems in bacteria. A) In gram-negative bacteria, QS is regulated by the generally called LuxI-LuxR system. The signal molecule homoserine lactone (HL) is synthesized by LuxI. When the HL reaches a threshold, it binds to the transcription regulator LuxR that regulates the expression of the target genes. B) In gram-positive bacteria, the regulation is driven by a two-component signal-transduction system. The signal molecules are usually small peptides either post-translationally modified or not, which are secreted through ABC exporter system (Ex). The molecule secreted binds to the receptor, a sensor kinase (SK) that autophosphorilate a histidine residue. Then, the phosphate group is transferred to the response regulator (RR) protein that may be a transcription factor therefore regulating the expression of the target genes. Production of antibiotics are under control of QS system, for example C) the β-lactam antibiotic carbapenem by the gram negative pathogen Erwinia carotovora, and D) the aminoglycoside antibiotic streptomycin by Streptomyces species.
Figure 2
Figure 2
Bacteria develop structurally complex communities called biofilms. Formation of biofilms responds to multiple factors and can be regulated by quorum sensing. These bacterial communities are formed by cells embedded within an extracellular matrix composed of proteins, exopolysaccharides and other molecules. This extracellular matrix confers stability and protect the cells from external aggressions as antibiotics. Biofilms of Bacillus subtilis grown in vitro develop: A) Top view of a pellicle in the interphase liquid-air in standing liquid culture and B) colony morphology in agarized medium and both characterized for the formation of typical wrinkles. C) A biofilm of Pseudomonas aeruginosa growth in agarized medium supplement with Congo Red appears as wrinkly colonies strongly stained red (Picture courtesy of Dr Liraz Chai).
Figure 3
Figure 3
Effect of rifampicin and oligomycin on development of S. coelicolor. Each well (edge visible at left) contains 60μl of a 20μg/ml solution of each drug. A) Rifampicin, a transcription inhibitor, causes a range of phenotypes across a diffusion gradient. This is visible as accelerated aerial hyphae and actinorhodin production near the well. B) The mitochondrial ATP synthase inhibitor oligomycin A causes a zone of growth inhibition, followed by an area of altered secondary metabolite production and aerial hyphe development. (Microscopy: Matt Traxler, Oligomycin A purified by Gavin Carr)
Figure 4
Figure 4
Examples of clinically relevant antibiotics used for treatment of important human diseases. A) Aminoglycosides are inhibitors of protein synthesis by targeting the ribosomal subunit 30S, B) β-lactams target the bacterial peptido-glycan, C) Macrolides target the ribosomal subunit 50S and block protein synthesis and D) Tetracyclines block the entrance of t-RNAs in bacterial ribosomes.
Figure 5
Figure 5
Natural small molecules produced by different microorganisms. A) Pyocyanin, the phenazin produces by P. aeruginosa, and the structural similar antibiotic quinolone with a role in the formation of wrinkled biofilms. B) Furanones (2-furanone) produced by different plants are structurally similar to QS signal molecules N-acyl-homoserine lactone or autorinducer-2, and therefore may interfere with the communication among bacteria. C) Surfactin, a lipopeptide produced by B. subtilis acts a signal molecule in the formation of stable biofilms of B. subtilis. Other structurally divergent molecules produced by other organisms, as nystatin, valinomycin or nisin induces similar response via the KinC sensor kinase.
Figure 6
Figure 6
Screening for isolates that cause developmental/morphological changes in S. coelicolor. First column: 5 ul of dense spore solutions of WT Streptomyces coelicolor M145 (alone in row 1) and various wild Streptomyces isolates were spotted 1 cm apart on R2YE agar. Isolates were screened for their ability to influence S. coelicolor morphology. Second column: Wild isolates were grown as lawns on agar, and extracted with ethanol. Extracts were then tested for morphological activity against a lawn of S. coelicolor (pictured) after 48 hours. Third column: Close-ups of the same wells shown in column 2 after 72 hours. Row one shows a control colony of S. coelicolor and a well with extract from an uninoculated plate. The extracts showed various activities against S. coelicolor (Figure provided by Matt Traxler).
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