Bacterial resistance against antibiotic treatment has become a major threat to public health. Antimicrobial peptides (AMPs) have emerged as promising alternative agents for treatment of infectious diseases. This study characterizes novel synthetic peptides sequentially derived from the AMP centrocin 1, isolated from the green sea urchin, for their applicability as anti-infective agents.The microbicidal effect of centrocin 1 heavy chain (CEN1 HC-Br), its debrominated analogue (CEN1 HC), the C-terminal truncated variants of both peptides, i.e. CEN1 HC-Br (1-20) and CEN1 HC (1-20), as well as the cysteine to serine substituted equivalent CEN1 HC (Ser) was evaluated using minimal microbicidal concentration assay. The anti-inflammatory properties were assessed by measuring the inhibition of secretion of pro-inflammatory cytokines. All the peptides tested exhibited marked microbicidal and anti-inflammatory properties. No difference in efficacy was seen comparing CEN1 HC-Br and CEN1 HC, while the brominated variant had higher cytotoxicity. C-terminal truncation of both peptides reduced salt-tolerability of the microbicidal effect as well as anti-inflammatory actions. Also, serine substitution of cysteine residue decreased the microbicidal effect. Thus, from the peptide variants tested, CEN1 HC showed the best efficacy and safety profile. Further, CEN1 HC significantly reduced bacterial counts in two different animal models of infected wounds, while Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) failed to develop resistance against this peptide under continued selection pressure. In summary, CEN1 HC appears a promising new antimicrobial agent, and clinical studies are warranted to evaluate the applicability of this AMP for local treatment of infections in man.

To assess the difference in the fate of the antibiotic colistin (COLI) after its pulmonary delivery as a powder or a solution, we developed a COLI powder and evaluated the COLI pharmacokinetic properties in rats after pulmonary administration of the powder or the solution. The amorphous COLI powder prepared by spray drying was characterized by a mass median aerodynamic diameter and fine particle fraction of 2.68 ± 0.07 µm and 59.5 ± 5.4%, respectively, when emitted from a Handihaler®. After intratracheal administration, the average pulmonary epithelial lining fluid (ELF): plasma area under the concentration versus time curves (AUC) ratios were 570 and 95 for the COLI solution and powder, respectively. However, the same COLI plasma concentration profiles were obtained with the two formulations. According to our pharmacokinetic model, this difference in ELF COLI concentration could be due to faster systemic absorption of COLI after the powder inhalation than for the solution. In addition, the COLI apparent permeability (Papp) across a Calu-3 epithelium model increased 10-fold when its concentration changed from 100 to 4000 mg/L. Based on this last result, we propose that the difference observed in vivo between the COLI solution and powder could be due to a high local ELF COLI concentration being obtained at the site where the dry particles impact the lung. This high local COLI concentration can lead to a local increase in COLI Papp, which is associated with a high concentration gradient and could produce a high local transfer of COLI across the epithelium and a consequent increase in the overall absorption rate of COLI.

The actinomycetes strains isolated from unexplored ecosystems are a promising alternative for the biosynthesis of novel antimicrobial compounds. Depending on the interesting antifungal activity of the studied strain S19, the statistical method seems to be an effective tool for optimizing the production of anticandidal molecules.

The rates of antimicrobial-resistant organisms (ARO) continue to increase for both hospitalized and community patients. Few resources have been allocated to reduce the spread of resistance on global, national and local levels, in part because the broader economic impact of antimicrobial resistance (i.e. the externality) is not fully considered when determining how much to invest to prevent AROs, including strategies to contain antimicrobial resistance, such as antimicrobial stewardship programs. To determine how best to measure and incorporate the impact of externalities associated with the antimicrobial resistance when making resource allocation decisions aimed to reduce antimicrobial resistance within healthcare facilities, we reviewed the literature to identify publications which 1) described the externalities of antimicrobial resistance, 2) described approaches to quantifying the externalities associated with antimicrobial resistance or 3) described macro-level policy options to consider the impact of externalities. Medline was reviewed to identify published studies up to September 2016.

Antimicrobial peptides (AMPs) are originally developed for anti-infective treatments. Because of their membrane-lytic property, AMPs have been considered as candidates of antitumor agents for a long time. However, their antitumor applications are mainly hampered by fast renal clearance and high systemic toxicities. This study proposes a strategy aiming at addressing these two issues by conjugating AMPs with porphyrins, which bind to albumin increasing AMPs' resistance against renal clearance and thus enhancing their antitumor efficacies. Porphyrins' photodynamic properties can further augment AMPs' antitumor effects. In addition, circulating with albumin ameliorates AMPs' systemic toxicities, i.e. hemolysis and organ dysfunctions. As an example, we conjugated an AMP, K6L9, with pyropheophorbide-a (PPA) leading to a conjugate of PPA-K6L9. PPA-K6L9 bound to albumin with a KD value at the sub-micromolar range. Combining computational and experimental approaches, we characterized the molecular interaction of PPA-K6L9 with albumin. Furthermore, PPA-conjugation promoted K6L9' antitumor effects by prolonging its in vivo retention time, and reduced the hemolysis and hepatic injuries, which confirmed our design strategy.

The objective of this systematic review with meta-analysis is to determine whether prophylactic local antibiotics prevent surgical site infections (SSIs) in instrumented spinal fusions and traumatic fracture repair. A secondary objective is to investigate the effect of vancomycin, a common local antibiotic of choice, on the microbiology of SSIs.

Owing to antibiotic resistance, alternative antimicrobials from medicinal plants are receiving attention as leads for anti-infective agents. This study aimed to investigate selected tree species and their constituents for activity against bacterial foodborne pathogens, particularly Salmonella serovars.

Bacterial resistance to most common antibiotics is a harbinger of the requirement to find novel anti-infective, antimicrobials agents, and increase innovative strategies to struggle them. Numerous bacteria produce small peptides with antimicrobial activities called bacteriocin. This study aimed to investigate the antibacterial properties of the fusion protein of Enterocin A and Colicin E1 modified against pathogens.

The prescription of topical antibiotics for the prevention of infections in uncomplicated wounds is common. However, the efficacy is not well reported. Therefore, the objective of the study was to conduct a systematic review and meta-analysis of the available evidence on prevention of uncomplicated wound infections by prophylactic topical antibiotics.

Scorpion venom constitutes a rich source of biologically active compounds with high potential for therapeutic and biotechnological applications that can be used as prototypes for the design of new drugs. The aim of this study was to characterize the structural conformation, evaluate the antimicrobial activity, and gain insight into the possible action mechanism underlying it, for two new analog peptides of the scorpion peptide Stigmurin, named StigA25 and StigA31. The amino acid substitutions in the native sequence for lysine residues resulted in peptides with higher positive net charge and hydrophobicity, with an increase in the theoretical helical content. StigA25 and StigA31 showed the capacity to modify their structural conformation according to the environment, and were stable to pH and temperature variation-results similar to the native peptide. Both analog peptides demonstrated broad-spectrum antimicrobial activity in vitro, showing an effect superior to that of the native peptide, being non-hemolytic at the biologically active concentrations. Therefore, this study demonstrates the therapeutic potential of the analog peptides from Stigmurin and the promising approach of rational drug design based on scorpion venom peptide to obtain new anti-infective agents.

Infective/bacterial endocarditis is a rare but life-threatening disease with a hospital mortality rate of 22.7% and a 1-year mortality rate of 40%. Therefore, continued research efforts to develop efficient anti-infective implant materials are of the utmost importance. Equally important is the development of test systems that allow the performance of new materials to be comprehensively evaluated. In this study, a novel antibacterial coating based on dalbavancin was tested in comparison to rifampicin/minocycline, and the suitability of a recently developed mouse tail vein model for testing the implant coatings was validated. Small polymeric stent grafts coated with a poly-L-lactic acid (PLLA) layer and incorporated antibiotics were colonized with Staphylococcus (S.) aureus before implantation into the tail vein of mice. The main assessment criteria were the hematogenous spread of the bacteria and the local tissue reaction to the contaminated implant. For this purpose, colony-forming units (CFU) in the blood, spleen and kidneys were determined. Tail cross sections were prepared for histological analysis, and plasma cytokine levels and expression values of inflammation-associated genes were examined. Both antibiotic coatings performed excellently, preventing the onset of infection. The present study expands the range of available methods for testing the anti-infectivity of cardiovascular implants, and the spectrum of agents for effective surface coating.

Osteomyelitis is typically a bacterial infection (usually from Staphylococcus) or, more rarely, a fungal infection of the bone. It can occur in any bone in the body, but it most often affects the long bones (leg and arm), vertebral (spine), and bones of the foot. Microbial success in osteomyelitis is due to their ability to form biofilms which inhibit the wound healing process and increases resistance to anti-infective agents. Also, biofilms do not allow easy penetration of antibiotics into their matrix making clinical treatment a challenge. The development of local antibiotic delivery systems that deliver high concentrations of antibiotics to the affected site is an emerging area of research with great potential. Standard treatment includes antibiotic therapy, either locally or systemically and refractory cases of osteomyelitis may lead to surgical intervention and a prolonged course of antibiotic treatment involving placement of antibiotic-doped beads or spacers within the wound site. There are disadvantages with this treatment modality including insufficient mixing of the antibiotic, lack of uniform bead size, resulting in lower antibiotic availability, and limitations on the antibiotics employed. Thus, a method is needed to address biofilm formations in the wound and on the surface of the surgical implants to prevent osteomyelitis. In this study, we show that all antibiotics studied were successfully doped into PMMA and antibiotic-doped 3D printed beads, disks, and filaments were easily printed. The growth inhibition capacity of the antibiotic-loaded PMMA 3D printed constructs was also demonstrated.

Targeting bacterial virulence mechanisms without compromising bacterial growth is a promising strategy to prevent drug resistance. LysR-type transcriptional regulators (LTTRs) possess structural conservation across bacterial species and regulate virulence in numerous pathogens, making them attractive targets for antimicrobial agents. We targeted AphB, a Vibrio cholerae LTTR, which regulates the expression of genes encoding cholera toxin and toxin-co-regulated pilus for inhibitor designing. Since AphB ligand is unknown, we followed a molecular fragment-based approach for ligand designing using FDA-approved drugs and subsequent screen to identify molecules that exhibited high-affinity binding to AphB ligand-binding pocket. Among the identified compounds, ribavirin, an anti-viral drug, antagonized AphB functions. Ribavirin perturbed Vibrio cholerae pathogenesis in animal models. The inhibitory effects of the drug was limited to the bacteria expressing wild type AphB, but not its constitutively active mutant (AphBN100E), which represents the ligand-bound state, suggesting that ribavirin binds to the active site of AphB to exert its inhibitory role and there exists no AphB-independent mechanism of its action. Similarly, ribavirin suppressed the functions of Salmonella Typhi LTTR Hrg, indicating its broad spectrum efficacy. Moreover, ribavirin did not affect the bacterial viability in culture. This study cites an example of drug repurposing for anti-infective therapy.

Bacitracin A (BA) is an excellent polypeptide antibiotic that is active against gram-positive bacteria without triggering multidrug resistance. However, BA is inactive against gram-negative bacteria because of its inability to cross the outer membrane of these cells, and it has strong nephrotoxicity, thus limiting its clinical applications. Nanoantibiotics can effectively localize antibiotics to the periplasmic space of bacteria while decreasing the adverse effects of antibiotics. In this study, biodegradable hydrophobic copolymers of poly (d,l-lactide-co-glycolide) (PLGA) were attached to the N-termini of BA to design a novel class of self-assembled nano-bacitracin A (nano-BAs), and their potential as antibacterial agents was evaluated in vitro and in vivo. Nano-BAs had a core-shell structure with a mean diameter <150 nm. Impressively, nano-BAs had strong antibacterial properties against both gram-positive and gram-negative bacteria, and the distribution of antibacterial activity as a function of PLGA block length was skewed toward longer PLGA chains. No cytotoxicity against HK-2 cells or human red blood cells (hRBCs) was observed in vitro, suggesting good biocompatibility. A high local density of BA mass on the surface promoted endocytotic cellular uptake, and hydrophobic interactions between the PLGA block and lipopolysaccharide (LPS) facilitated the uptake of nano-BAs, thereby leading to greater antibacterial activities. In addition, Nano-BA5K was found to be effective in vivo, and it served as an anti-infective agent for wound healing. Collectively, this study provides a cost-effective means of developing self-assembling nano-polypeptide antibiotic candidates with a broader antibacterial spectrum and a lower toxicity than commercially available peptide antibiotics, owing to their modification with biodegradable copolymers.