Current Topics in Medicinal Chemistry - Volume 18, Issue 24, 2018

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.

The use of antibiotics has revolutionized medicine, greatly improving our capacity to save millions of lives from otherwise deadly bacterial infections. Unfortunately, the health-associated benefits provided by antibiotics have been counteracted by bacteria developing or acquiring resistance mechanisms. The negative impact to public health is now considered of high risk due to the rapid spreading of multi-resistant strains. More than 60 % of clinically relevant antibiotics of natural origin target the ribosome, the supramolecular enzyme which translates the genetic information into proteins. Although many of these antibiotics bind the small ribosomal subunit, only a few are reported to inhibit the initiation of protein synthesis, with none reaching commercial availability. Counterintuitively, translation initiation is the most divergent phase of protein synthesis between prokaryotes and eukaryotes, a fact which is a solid premise for the successful identification of drugs with reduced probability of undesired effects to the host. Such a paradox is one of its kind and deserves special attention. In this review, we explore the inhibitors that bind the 30S ribosomal subunit focusing on both the compounds with proved effects on the translation initiation step and the underreported translation initiation inhibitors. In addition, we explore recent screening tests and approaches to discover new drugs targeting translation.

O-Prenylphenylpropanoids represent a group of rare natural products. During the last twenty years, such phytochemicals have been revealed to possess a great pharmacological potential. These compounds have been obtained for the most part from plant species of the Rutaceae, Apiaceae, and Fabaceae families, as well as from fungi and bacteria. In this review we wish to detail the state of the art about O-prenylphenylpropanoids having in vitro and in vivo anti-microbial properties from different points of view. The herein cited natural products are effective in inhibiting the virulence of human oral pathogens.

As the resistance to antimicrobial molecules increases among bacteria, the need for new antimicrobial molecules increases. Antimicrobial peptides (AMP), which may be a new generation of antibiotic candidates, are important in this respect. AMPs are small, cationic and amphipathic peptide sequences. In eukaryotes, they are synthesized as a part of the immune system. Substantially, AMPs are discovered in all kingdoms of life such as bacteria, fungi and protozoa. Approximately 3,000 AMPs have been reported in the literature. However, most of these AMPs have been synthesized through chemical synthesis. Nature has a huge source of microorganisms, and in the literature, there is a tendency to increase every year the number of bacteria and fungus-derived AMPs thanks to their biotechnological importance. The exploration of AMP and antibiofilm peptide (ABP) producer microorganisms brings with it a lot of challenges experimentally. In this review study, we want to highlight the importance and challenge of these natural peptides derived from microorganisms. We will also propose a new explanation for ABPs.

Recently gut bacterial populations seem to be involved in many functions and in the pathogenesis of several medical conditions. Traditionally the intestinal microbiome has been recognized to play an important role in metabolizing food compounds in simpler chemical structures for the absorption of different nutrients, and in maintenance control of gastrointestinal pathogens species. Bacterial populations are implicated in a complicated network of interactions within the immune system, epithelial cells local endocrine system, that affects the peripheral and the central nervous system, via blood circulation. Microbiome influencing the mind via immune, endocrine and metabolic signalling, is able to exert some clinical effects in different mental diseases. It releases endocrine substances through several pathways involved in the modulation of neuroinflammation and production of several neurotrasmitter precursors. It has recently been named psychobiome. It is known that phenolic compounds are able to influence microbiome proliferation and to exert several roles, especially regarding neuroinflammation in depressive and anxious behaviour. The clinical effects are reported in the literature. The aim of this study is to highlight the interaction between polyphenols and microbiota- gut-brain axis.

Background: Antimicrobial research is being focused to look for more effective therapeutics against antibiotic-resistant infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In this direction, antimicrobial peptides (AMP) appear as promising tool. Objectives: This study evaluated the antimicrobial activity of different AMPs (Citropin 1.1, Temporin A, Pexiganan, CA(1–7)M(2–9)NH2, Pal-KGK-NH2, Pal-KKKK-NH2, LL-37) against human MRSA clinical isolates. Methods: The Minimum Inhibitory Concentration (MIC) was assessed for each AMP; then, the most active ones (Citropin 1.1, Temporin A, CA(1–7)M(2–9)NH2 and Pal-KGK-NH2) were tested against selected MRSA strains by time-kill studies. Results: The lowest MIC value was observed for Pal-KGK-NH2 (1 μg/ml), followed by Temporin A (4- 16 μg/ml), CA(1–7)M(2–9)NH2 (8-16 μg/ml) and Citropin 1.1 (16-64 μg/ml), while higher MICs were evidenced for LL-37, Pexiganan and Pal-KKKK-NH2 (> 128 μg/ml). In time-kill experiments, Citropin 1.1 and CA(1-7)M(2-9)NH2 showed a relatively high percentage of growth inhibition (>30 %) for all the tested MRSA clinical isolates, with a dose-dependent activity resulting in the highest percentage of bacterial Conclusion: Overall, our data demonstrated the potential of some AMPs against MRSA isolates, such as Citropin 1.1 and CA(1-7)M(2-9)NH2, that represents a promising area of development for different clinical applications.

Background: Pseudomonas aeruginosa is a gram-negative pathogen, associated with a severe mortality rate. It is also difficult to treat due to numerous resistance mechanisms to a wide range of antibiotics. Objective: Evaluate the activity of pexiganan, an antimicrobial peptide, in combination with two clinical antibiotics (azithromycin and tigecycline) that are not active against P. aeruginosa. Methods: Ten clinical P. aeruginosa were isolated from urinary tract infections, blood culture, skin infections and respiratory tract infections. Minimum inhibitory concentrations (MICs) and synergies were evaluated by broth microdilution, checkerboard assays and time-kill studies. In vitro synergy was confirmed with an in vivo experiment using a murine model of sepsis. Results: Pexiganan MICs were included between 2 and 16 mg/L. Tigecycline and azithromycin MICs were high as expected (4-64 mg/L and 32-256 mg/L, respectively). Pexiganan and azithromycin combination resulted to be additive or indifferent while tigecycline and pexiganan combination was synergic against seven out of ten P. aeruginosa and additive against the other strains. In vivo experiment confirmed the in vitro synergy, denoting a significative reduction of bacteria in mice treated with pexiganan and tigecycline combination. Conclusion: Antimicrobial peptides are molecules that could be useful in the fight against infections and pexiganan seems to be one of the most promising. Our results demonstrated that, in association with tigecycline, pexiganan administration could overcome antibiotic resistance and increase the effectiveness of treatment against P. aeruginosa sepsis.