Some bacterial pathogens elaborate and secrete virulence factors in response to environmental signals, others in response to a specific host product, and still others in response to no discernible cue. In this study, we have demonstrated that the synthesis of Staphylococcus aureus virulence factors is controlled by a density-sensing system that utilizes an octapeptide produced by the organism itself. The octapeptide activates expression of the agr locus, a global regulator of the virulence response. This response involves the reciprocal regulation of genes encoding surface proteins and those encoding secreted virulence factors. As cells enter the postexponential phase, surface protein genes are repressed by agr and secretory protein genes are subsequently activated. The intracellular agr effector is a regulatory RNA, RNAIII, whose transcription is activated by an agr-encoded signal transduction system for which the octapeptide is the ligand.

Cell Density Control of Staphylococcal Virulence Mediated by an Octapeptide Pheromone

Microcins, gene-encoded antibacterial peptides from enterobacteria

Summary
Because of the emergence of antibiotic-resistant pathogens worldwide, a number of infectious diseases have become difficult to treat. This threatening situation is worsened by the fact that very limited progress has been made in developing new and potent antibiotics in recent years. However, a group of antimicrobials, the so-called bacteriocins, have been much studied lately because they hold a great potential in controlling antibiotic-resistant pathogens. Bacteriocins are small antimicrobial peptides (AMPs) produced by numerous bacteria. They often act toward species related to the producer with a very high potency (at pico- to nanomolar concentration) and specificity. The common mechanisms of killing by bacteriocins are destruction of target cells by pore formation and/or inhibition of cell wall synthesis. Several studies have revealed that bacteriocins display great potential in the medical sector as bacteriocinogenic probiotics and in the clinic as therapeutic agents. In this review, we discuss the emerging antibiotic resistance and strategies to control its dissemination, before we highlight the potential of AMPs from bacteria as a new genre of antimicrobial agents.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2672.2012.05338.x

Natural antimicrobial peptides from bacteria: characteristics and potential applications to fight against antibiotic resistance.

Will new generations of modified antimicrobial peptides improve their potential as pharmaceuticals

Within the repertoire of antibiotics available to a prescribing clinician, the majority affect a broad range of microorganisms, including the normal flora. The ecological disruption resulting from antibiotic treatment frequently results in secondary infections or other negative clinical consequences. To address this problem, our laboratory has recently developed a new class of pathogen-selective molecules, called specifically (or selectively) targeted antimicrobial peptides (STAMPs), based on the fusion of a species-specific targeting peptide domain with a wide-spectrum antimicrobial peptide domain. In the current study, we focused on achieving targeted killing of Streptococcus mutans, a cavity-causing bacterium that resides in a multispecies microbial community (dental plaque). In particular, we explored the possibility of utilizing a pheromone produced by S. mutans, namely, the competence stimulating peptide (CSP), as a STAMP targeting domain to mediate S. mutans-specific delivery of an antimicrobial peptide domain. We discovered that STAMPs constructed with peptides derived from CSP were potent against S. mutans grown in liquid or biofilm states but did not affect other oral streptococci tested. Further studies showed that an 8-amino-acid region within the CSP sequence is sufficient for targeted delivery of the antimicrobial peptide domain to S. mutans. The STAMPs presented here are capable of eliminating S. mutans from multispecies biofilms without affecting closely related noncariogenic oral streptococci, indicating the potential of these molecules to be developed into “probiotic” antibiotics which could selectively eliminate pathogens while preserving the protective benefits of a healthy normal flora.

Targeted killing of Streptococcus mutans by a pheromone-guided "smart" antimicrobial peptide.

We constructed a peptide consisting of a staphylococcal AgrD1 pheromone fused to the channel-forming domain of colicin Ia and named it pheromonicin. This fusion peptide had bactericidal effects against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA, respectively), but not against Staphylococcus epidermidis or Streptococcus pneumoniae. Growth rates, vital staining and colony forming unit (CFU) counts showed that pheromonicin did not merely suppress growth but killed S. aureus cells. The specificity of pheromonicin was shown by the absence of bactericidal effects against an accessory gene regulator (agr) locus knockout of S. aureus, and a dose-dependent inhibition of the bactericidal effects of pheromonicin by competition with corresponding free AgrD pheromone. In vivo, all pheromonicin-treated mice survived administration of MRSA that was lethal to controls. No toxicity was detectable in human liver or renal cells in culture, or in livers, kidneys or spleens of pheromonicin-treated mice. The results suggest that these types of chimeric peptides may be of value as antibiotics against specific bacterial infections.

/pdf/an-engineered-multidomain-bactericidal-peptide-as-a-model-2epu269dao.pdf

An engineered multidomain bactericidal peptide as a model for targeted antibiotics against specific bacteria.

Nat. Biotechnol. 21, 1480–1485 (2003) On page 1481, two symbols in the key for Figure 2h were reversed; the solid circle should refer to PEN, and the solid triangle to PMC.

/pdf/correction-corrigendum-an-engineered-multidomain-4bbl4c0668.pdf

Gang Cheng

Papers

An engineered multidomain bactericidal peptide as a model for targeted antibiotics against specific bacteria.

Correction: Corrigendum: An engineered multidomain bactericidal peptide as a model for targeted antibiotics against specific bacteria