RNAIII Inhibiting Peptide (RIP) and Derivatives as Potential Tools for the Treatment of S. aureus Biofilm Infections.

S. aureus under the biofilm mode of growth is often related to several nosocomial infections, more frequently associated with indwelling medical devices (catheters, prostheses, portacaths or heart valves). As a biofilm, the biopolymer matrix provides an excellent growth medium, increasing the tolerance to antibiotics and host immune system. To date, the antimicrobial therapy alone is not effective. A novel strategy to prevent biofilm formation is based on the interference with the bacterial cell-cell communication, a process known as quorum sensing (QS) and mediated by the RNA-III-activating peptide (RAP) and its target protein TRAP (Target of RAP). The RNAIII inhibiting peptide (RIP) is able to inhibit S. aureus pathogenesis by disrupting QS mechanism competing with RAP, thus inhibiting the phosphorylation of TRAP. This alteration leads to a reduced adhesion and to the inhibition of RNAIII synthesis, with the subsequent suppression of toxins synthesis. The present paper will provide an overview on the activity and potential applications of RIP as biofilm inhibiting compound, useful in the management of S. aureus biofilm infections. Moreover, medicinal chemistry strategies have been examined to better understand which modifications and/or structure alterations were able to produce new derivatives of this QS inhibitor with an improved antibiofilm activity.

Transcriptome-Based Analysis in Lactobacillus plantarum WCFS1 Reveals New Insights into Resveratrol Effects at System Level.

SCOPE: This study was undertaken to expand our insights into the mechanisms involved in the tolerance to resveratrol (RSV) that operate at system-level in gut microorganisms and advance knowledge on new RSV-responsive gene circuits. METHODS AND RESULTS: Whole genome transcriptional profiling was used to characterize the molecular response of Lactobacillus plantarum WCFS1 to RSV. DNA repair mechanisms were induced by RSV and responses were triggered to decrease the load of copper, a metal required for RSV-mediated DNA cleavage, and H2 S, a genotoxic gas. To counter the effects of RSV, L. plantarum strongly up- or downregulated efflux systems and ABC transporters pointing to transport control of RSV across the membrane as a key mechanism for RSV tolerance. L. plantarum also downregulated tRNAs, induced chaperones, and reprogrammed its transcriptome to tightly control ammonia levels. RSV induced a probiotic effector gene and a likely deoxycholate transporter, two functions that improve the host health status. CONCLUSION: Our data identify novel protective mechanisms involved in RSV tolerance operating at system level in a gut microbe. These insights could influence the way RSV is used for a better management of gut microbial ecosystems to obtain associated health benefits.

Targeting the Mycobacterium tuberculosis 30/32-kDa mycolyl transferase complex as a therapeutic strategy against tuberculosis: Proof of principle by using antisense technology.

We have investigated the effect of sequence-specific antisense phosphorothioate-modified oligodeoxyribonucleotides (PS-ODNs) targeting different regions of each of the 3032-kDa protein complex (antigen 85 complex) encoding genes on the multiplication of Mycobacterium tuberculosis. Single PS-ODNs to one of the three mycolyl transferase transcripts, added either once or weekly over the 6-wk observation period, inhibited bacterial growth by up to 1 log unit. A combination of three PS-ODNs specifically targeting all three transcripts inhibited bacterial growth by approximately 2 logs; the addition of these PS-ODNs weekly for 6 wk was somewhat more effective than a one-time addition. Targeting the 5' end of the transcripts was more inhibitory than targeting internal sites; the most effective PS-ODNs and target sites had minimal or no secondary structure. The effect of the PS-ODNs was specific, as mismatched PS-ODNs had little or no inhibitory activity. The antisense PS-ODNs, which were highly stable in M. tuberculosis cultures, specifically blocked protein expression by their gene target. PS-ODNs targeting the transcript of a related 24-kDa protein (mpt51) had little inhibitory effect by themselves and did not increase the effect of PS-ODNs against the three members of the 3032-kDa protein complex. The addition of PS-ODNs against the transcripts of glutamine synthetase I (glnA1) and alanine racemase (alr) modestly increased the inhibitory efficacy of the 3032-kDa protein complex-specific PS-ODNs to approximately 2.5 logs. This study shows that the three mycolyl transferases are highly promising targets for antituberculous therapy by using antisense or other antimicrobial technologies.