Host defense peptides (HDPs) possess both direct bacteriocidal and immunomodulatory activities. In this study, chicken cathelicidin-1 (cCATH-1) and chicken cathelicidin-3 (cCATH-3) were selected based on their markedly different minimum inhibitory concentrations (MICs) against avian pathogenic Escherichia coli (APEC) strains, with MICs of cCATH-1 being 4- to 16-fold lower than those of cCATH-3. However, following intraperitoneal challenge with APEC strain E058 (4 × 10[6] CFU/mouse), 80% of cCATH-3 treated mice survived while 20% of cCATH-1 treated mice survived. Flow cytometry (FC) revealed significantly lower peripheral blood Ly6C[high] monocytes but higher peritoneal Ly6C[high] macrophages in cCATH-3-treated mice at 4 and 8 h post-treatment. Peritoneal CCL3 secretion was significantly upregulated in cCATH-3 treated mice at 8 h post-treatment. Upon knockout of macrophages, the protection of cCATH-3 in mice against APEC E058 challenge was markedly abolished. In vitro, peritoneal macrophages treated with cCATH-3 showed stronger bacteriocidal activity than those treated with cCATH-1. Mouse CCL-3 (mCCL3)-specific antibody neutralize the effect of mCCL3 on macrophages chemotaxis in vitro. mCCL3-specific antibody administration resulted in 0% survival in cCATH-3-treated mice versus 60% survival in cCATH-3-treated mice administered with mock antibody, while cCATH-1-treated mice showed 0% survival administered with either mCCL3-specific antibody or mock antibody after APEC E058 strain challenge. In summary, cCATH-3 provides robust protection against APEC infection compared with cCATH-1 in mice, partially through CCL3-mediated macrophage chemotaxis and enhanced bacteriocidal activity in activated macrophages, revealing a novel mechanism of avian cathelicidins and supporting HDPs as alternatives to antibiotics for controlling avian colibacillosis.

Tuberculosis (TB), a highly lethal infectious diseases induced by Mycobacterium tuberculosis (Mtb) infection, continues to be a major challenge in the realm of infectious diseases. Functional circular RNAs (circRNAs) have been extensively reported to play crucial immunological regulatory roles in Mtb infection and TB development. Our previous researches have demonstrated that CircRNA TRAPPC6B (circTRAPPC6B) can enhance autophagy in Mtb infected macrophages to facilitate intracellular Mtb inhibition/clearance, while how to expand the potential of circTRAPPC6B for effective anti-TB treatment remains a considerable challenge. Here, we innovated a novel macrophage-targeted exosome system, designated as Man-Rif@CircRNA@Exo, which encapsulates circTRAPPC6B and rifampicin to synchronize targeted antibiotic killings and host immunological defenses against Mtb. Man-Rif@CircRNA@Exo exhibited selective macrophage targeting effects attributable to mannose modification and then accumulated into lysosomes of macrophages. Furthermore, Man-Rif@CircRNA@Exo treatment significantly increased intracellular circTRAPPC6B level, which in turn promoted autophagy of Mtb infected macrophages, thereby accelerating host immunological clearance of Mtb. Collectively, Man-Rif@CircRNA@Exo indicated enhanced intracellular Mtb killing efficiency by synergizing targeted rifampicin bacteriocidal action with autophagy-mediated host immunological clearance against Mtb. This synergistic anti-TB approach significantly reduced Mtb burdens and alleviated tissue pathology and inflammation in the lungs of Mtb-infected mice, without significantly affecting liver/kidney structure and functional parameters to show acceptable safety. These results highlight the promising potential of Man-Rif@CircRNA@Exo to synchronize targeted antibiotic action and host immunological defenses for more effective anti-TB treatment, which is anticipated to advance the development of novel host directed therapeutics against TB and drug-resistant TB.

The increasing risk of drug-resistant infections and unexpected pandemics like Covid-19 has prompted researchers to explore the area of drug repurposing. Natural products, being a result of the evolutionary optimisation processes can be potential starting points for such drug discovery programs. One such unexplored chemical is terrein, a secondary fungal metabolite. Although discovered in 1935 from Aspergillus terreus, the therapeutic potential of terrein has largely remained undeciphered. Research has primarily been focused on its biosynthetic pathways and its mycotoxic effects. However, in the last two decades, its biological properties including anticancer, anti-inflammatory anti-melanogenic, and bacteriocidal activities have been reported. These reports are preliminary in nature and do not adequately establish its overall therapeutic application. From its structural and therapeutic properties, it can be conjectured that terrein may act as a novel multimodal therapeutic. This comprehensive study reviews the synthesis, production and application aspects of terrein to understand its importance.

Colicins are antimicrobial proteins produced by certain strains of Escherichia coli that function as offensive weapons against closely-related competitor strains. Their bactericidal properties and narrow bacterial targeting range has made them of therapeutic interest. Furthermore, the applications of engineered non-bactericidal colicins are of interest as a cell surface-directed protein anchor for decorating E. coli with biomolecules. We previously demonstrated that an engineered non-bacteriocidal colicin E9 could be used to label bacterial cells with multiple biomolecules including glycans. Herein we extend our approach to colicin Ia, constructing mannose-presenting colicin la neoglycoproteins, through N-terminal organocatalyst-mediated protein aldol ligation (OPAL), or maleimide ligation targeting an internal cysteine. This work further highlights the potential utility of engineered colicins for non-genetic glyco-engineering of the E. coli cell surface.

Biologically mediated synthesis of nanomaterials has emerged as an ecologically benign and biocompatible approach. Our study explores enzymatic synthesis, utilizing α-amylase to synthesize ZnO nanoflowers (ZnO-NFs). X-ray diffraction and energy-dispersive X-ray spectroscopy revealed crystal structure and elemental composition. Dynamic light scattering analysis indicates that ZnO-NFs possess a size of 101 nm. Transmission electron microscopy showed a star-shaped morphology of ZnO-NFs with petal-like structures. ZnO-NFs exhibit potent photocatalytic properties, degrading 90% eosin, 87% methylene blue, and 81% reactive red dyes under UV light, with kinetics fitting the Langmuir-Hinshelwood pseudo-first-order rate law. The impact of pH and interfering substances on dye degradation was explored. ZnO-NFs display efficient bacteriocidal activity against different Gram-positive and negative strains, antibiofilm potential (especially with P. aeruginosa), and hemocompatibility up to 600 ppm, suggesting versatile potential in healthcare and environmental remediation applications.

The mode of action of antibiotics can be broadly classified as bacteriostatic and bactericidal. The bacteriostatic mode leads to the arrested growth of the cells, while the bacteriocidal mode causes cell death. In this work, we report the applicability of deuterium stable isotope probing (DSIP) in combination with Raman spectroscopy (Raman DSIP) for discriminating the mode of action of antibiotics at the community level. Escherichia coli, a well-known model microbe, was used as an organism for the study. We optimized the concentration of deuterium oxide required for metabolic activity monitoring without compromising the microbial growth. Our findings suggest that changes in the intensity of the C-D band in the high-wavenumber region could serve as a quantifiable marker for determining the antibiotic mode of action. This can be used for early identification of the antibiotic's mode of action. Our results explore the new perspective that supports the utility of deuterium-based vibrational tags in the field of clinical spectroscopy. Understanding the antibiotic's mode of action on bacterial cells in a short and objective manner can significantly enhance the clinical management abilities of infectious diseases and may also help in personalized antimicrobial therapy.

Antimicrobial peptides (AMPs) show promise as alternatives to traditional antibiotics for treating drug-resistant infections. Their adaptability and diverse sequence possibilities allow for rational design by modulating physicochemical determinants to achieve desired biological properties, transforming them into peptides for potential new therapies. Nisin, one of the best-studied AMPs, is believed to have potential to be used as a therapeutic, particularly against antibiotic-resistant bacteria. However, its instability in physiological conditions limits its use in clinical applications and pharmaceutical development. Exploration of new natural variants of nisin has uncovered diverse properties using different domains. Shuffling peptide modules can fine-tune the chemical properties of these molecules, potentially enhancing stability while maintaining or improving antimicrobial activity. In this study, hybrid AMPs were created by combining domains from three unique nisin variants, i.e. nisin A, cesin and rombocin, leading to the identification of a promising variant, named cerocin A, which harbours only 25 amino acids compared to the typical 31-35 amino acid length of nisin. Cerocin A demonstrates potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), approaching that of nisin itself. Cerocin A's mode of action involves a dual mechanism through the combination of two domains, consisting of a small ring/domain (6 amino acids) from the C-terminal end of rombocin attached to the preceding peptide of cesin, changing it from a bacteriostatic to a bactericidal peptide. Further mutation studies identified a new variant, cerocin V, with significantly improved resistance against trypsin degradation, while maintaining high potency. Importantly, cerocin V showed no undesired toxic effects on human red blood cells and remained stable in human plasma. In conclusion, we demonstrate that peptide construction using domain engineering is an effective strategy for manipulating both biological and physicochemical aspects, leading to the creation of novel bioactive molecules with desired properties. These constructs are appealing candidates for further optimization and development as novel antibiotics.

Staphylococcus aureus (S. aureus) causes many infections with significant morbidity and mortality. S. aureus can form biofilms, which can cause biofilm-associated diseases and increase resistance to many conventional antibiotics, resulting in chronic infection. It is critical to develop novel antibiotics against staphylococcal infections, particularly those that can kill cells embedded in biofilms. This study aimed to investigate the bacteriocidal and anti-biofilm activities of thiazolidinone derivative (TD-H2-A) against S. aureus. A total of 40 non-duplicate strains were collected, and the minimum inhibitory concentrations (MICs) of TD-H2-A were determined. The effect of TD-H2-A on established S. aureus mature biofilms was examined using a confocal laser scanning microscope (CLSM). The antibacterial effects of the compound on planktonic bacteria and bacteria in mature biofilms were investigated. Other characteristics, such as cytotoxicity and hemolytic activity, were researched. A mouse skin infection model was used, and a routine hematoxylin and eosin (H&E) staining was used for histological examination. The MIC values of TD-H2-A against the different S. aureus strains were 6.3-25.0 µg/mL. The 5 × MIC TD-H2-A killed almost all planktonic S. aureus USA300. The derivative was found to have strong bacteriocidal activity against cells in mature biofilms meanwhile having low cytotoxicity and hemolytic activity against Vero cells and human erythrocytes. TD-H2-A had a good bacteriocidal effect on S. aureus SA113-infected mice. In conclusion, TD-H2-A demonstrated good bacteriocidal and anti-biofilm activities against S. aureus, paving the way for the development of novel agents to combat biofilm infections and multidrug-resistant staphylococcal infections.IMPORTANCEStaphylococcus aureus, a notorious pathogen, can form a stubborn biofilm and develop drug resistance. It is crucial to develop new anti-infective therapies against biofilm-associated infections. The manuscript describes the new antibiotic to effectively combat multidrug-resistant and biofilm-associated diseases.

Bacterial cells can form biofilm on food contact surfaces, becoming a source of food contamination with profound health implications. The current study aimed to determine some Egyptian medicinal plants antibacterial and antibiofilm effects against foodborne bacterial strains in milk plants. Results indicated that four ethanolic plant extracts, Cinnamon (Cinnamomum verum), Chamomile (Matricaria chamomilla), Marigold (Calendula officinalis), and Sage (Salvia officinalis), had antibacterial (12.0-26.5 mm of inhibition zone diameter) and antibiofilm (10-99%) activities against Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes and Salmonella Typhimurium. The tested extracts had minimum inhibitory concentration values between 0.14 and 2.50 mg/ml and minimum bactericidal concentration values between 0.14 and 12.50 mg/ml. L. monocytogenes was more sensitive for all tested ethanolic extracts; Sage and Cinnamon showed a bacteriocidal effect, while Chamomile and Marigold were bacteriostatic. The ethanolic extracts mixture from Chamomile, Sage, and Cinnamon was chosen for its antibiofilm activity against L. monocytogenes using L-optimal mixture design. Gas chromatography and mass spectrometry analysis showed that this mixture contained 12 chemical compounds, where 2-Propenal,3-phenyl- had the maximum area % (34.82%). At concentrations up to 500 µg/ml, it had no cytotoxicity in the normal Vero cell line, and the IC50 value was 671.76 ± 9.03 µg/ml. Also, this mixture showed the most significant antibacterial effect against detached L. monocytogenes cells from formed biofilm in stainless steel milk tanks. At the same time, white soft cheese fortified with this mixture was significantly accepted overall for the panelist (92.2 ± 2.7) than other cheese samples, including the control group.

Natural killer cells (NKs) found during pregnancy at the maternal-fetal interface named decidual (d)NKs, show signs of education following first pregnancy, resulting in better placentation and fetus-growth, hence termed pregnancy trained dNKs (PTdNKs). Here we show that PTdNKs provide increased protection of the fetus from Fusobacterium nucleatum (FN) infection. We demonstrate that PTdNKs secrete elevated amounts of the bacteriocidal protein granulysin (GNLY) upon incubation with FN compared to dNKs derived from first pregnancies, which leads to increased killing of FN. Furthermore, we showed mechanistically that the GNLY secretion is mediated through the interaction of the FN's Fap2 protein with Gal-GalNAc present on PTdNKs. Finally, we show in vivo, using GNLY-tg mice that enhanced protection of the fetuses from FN infection is observed, as compared to wild type and that this enhance protection is NK cell dependent. Altogether, we show a new function for PTdNKs as protectors of the fetus from bacterial infection.

Periprosthetic infection is a devastating postimplantation complication in which a biofilm layer harboring invasive microorganisms forms around orthopedic implants, leading to severe implant failure and patient morbidity. Despite the development of several infection-triggered antibiotic release approaches, most current antibacterial coatings are susceptible to undesired antibiotic leakage or mechanical disintegration during prosthesis installation. Herein, we propose a self-controllable proteinic antibacterial coating capable of both long-lasting adherence onto titanium implant substrates over the implant fixation period and instantaneous bacterial eradication. Importantly, the pH-dependent reversible metal coordination of mussel adhesive protein (MAP) enabled bacterial concentration-dependent antibiotic delivery in response to infection-induced acidification. In addition, the MAP coating exhibited superior self-healable adhesive properties and scratch resistance, which enabled to avert issues associated with mechanical damages, including peeling and cracking, often occurring in conventional implant coating systems. The gentamicin-loaded MAP coating exhibited complete inhibition of bacterial growth in vivo against Staphylococcus aureus penetrations during implantation surgery (immediate infection) and even 4 weeks after implantation (delayed infection). Thus, our antibiotic-loaded MAP hydrogel coating can open new avenues for self-defensive antibiotic prophylaxis to achieve instant and sustainable bacteriocidal activity in orthopedic prostheses. © 2017 Elsevier Inc. All rights reserved.

Due to the multilayer structure of skin tissue, the fabrication of a 3-layer scaffold could result in planned dermal regeneration. Herein, polyurethane (PU) and polycaprolactone (PCL), as a function of their mechanical stability and collagen due to its arginine-glycine-aspartic acid sequences, zinc ions because of overcoming the common problems of biological factors were employed. The scaffolds' physical, mechanical, and biological properties were examined by SEM, FTIR, contact angle, mechanical tensile, bacteriocidal efficacy, and hemolysis. Also, after L-929 fibroblast seeding, their biological activity was determined by SEM, DAPI, and MTT assays. Then, the cell-seeded scaffolds were implanted in full-thickness wounds of rats and evaluated by wound closure, histological, and molecular techniques. The in vivo studies showed better wound closure with the composite scaffold containing zinc ions. While its dermal re-organization was retarded in the presence of zinc ions compared to the composite scaffold containing non-doped bioglass. Despite this, the doped composite scaffold indicated better observations with the histological evaluations than the nontreated and bare scaffold groups. Real-time PCR confirmed the higher expression of FGF2 and FGFR genes in rats treated with the zinc-doped composite scaffold. In conclusion, PU/PCL-collagen/PCL-collagen containing the doped or non-doped nanoparticles showed better potential to heal dermal injuries.

Hybrid metal halide semiconductors are a unique family of materials with immense potential for numerous applications. For this to materialize, environmental stability and toxicity deficiencies must be simultaneously addressed. We report here a porous, visible light semiconductor, namely, (DHS)Bi2I8 (DHS = [2.2.2] cryptand), which consists of nontoxic, earth-abundant elements, and is water-stable for more than a year. Gas- and vapor-sorption studies revealed that it can selectively and reversibly adsorb H2O and D2O at room temperature (RT) while remaining impervious to N2 and CO2. Solid-state NMR measurements and density functional theory (DFT) calculations verified the incorporation of H2O and D2O in the molecular cages, validating the porous nature. In addition to porosity, the material exhibits broad band-edge light emission centered at 600 nm with a full width at half-maximum (fwhm) of 99 nm, which is maintained after 6 months of immersion in H2O. Moreover, (DHS)Bi2I8 exhibits bacteriocidal action against three Gram-positive and three Gram-negative bacteria, including antibiotic-resistant strains. This performance, coupled with the recorded water stability and porous nature, renders it suitable for a plethora of applications, from solid-state batteries to water purification and disinfection.

"Hyperbaric oxygen therapy (HBO2T) is neither necessary nor recommended for the support of normal, uncompromised grafts or flaps. However, in tissue compromised by irradiation or in other cases where there is decreased perfusion or hypoxia, HBO2T has been shown to be extremely useful in flap salvage. Hyperbaric oxygen can help maximize the viability of the compromised tissue thereby reducing the need for regrafting or repeat flap procedures". This is the official stance of the Society of Undersea and Hyperbaric Medicine which is the international organization that sets standards for indications and implementation of hyperbaric medicine. A skin graft or flap involves transferring healthy skin, either full thickness or partial thickness, to a denuded area of the body to aid in healing. There are free-transfer grafts where skin, usually partial thickness, is removed from one area and placed at a more distant site, and there are rotation flaps. Rotation flaps are done by surgically freeing a full thickness amount of skin and rotating it to a nearby location. This involves preserving the native blood supply. Care must be taken with these graft so as not to compromise this native blood supply either from undue tension or torsion of the pedicle. Hyperbaric medicine has been shown to be useful in improving healing and providing higher success rates in compromised grafts and flaps. Hyperbaric oxygen therapy has several effects that are beneficial for healing these compromised grafts. It has been proven that HBO2 therapy will increase the oxygen carrying capacity of plasma up to 7%. This has been shown to be adequate to keep swine alive after all of their red blood cells have been removed. Hyperbaric oxygen therapy will result in increasing neovascularization and decrease tissue edema. This combination will improve the tissue environment in areas of vascular compromise. Hyperbaric oxygen effects are also advantageous in situations of crush injuries with grafts. These situations result in large amounts of edema, compromising any grafts done in these locations. Burn patients often require skin grafting. The burn setting presents with several complex processes that can compromise graft healing. Burns cause a hypercoagulable state in the microvascular. This will impede oxygen supply to these areas. HBO2 therapy increases neovascularization, thus improving blood supply to compromised areas. The increased oxygen-carrying capacity of the plasma will also aid in decreasing destruction of borderline tissues as time progresses. Localized edema is decreased with HBO2 therapy, which decreases tissue pressure and increases microvascular blood flow. Burn patients are susceptible to infections. HBO2 therapy helps lower infection rates by oxygen's bacteriostatic and bacteriocidal effect on certain microorganisms. Higher tissue oxygen content also neutralizes exotoxins. [1]

Hyperbaric oxygen therapy (HBO2) has many uses. The Undersea and Hyperbaric Medical Society is the international body that sets standards for the use of hyperbaric medicine. There are currently 14 approved indications for hyperbaric medicine and many more unapproved conditions where hyperbaric oxygen therapy may be useful. Hyperbaric oxygen therapy consists of placing a patient into a pressurized chamber of up to 3 atmospheres (ATM) of pressure. The surrounding ambient pressure at sea level is 1 ATM. Each additional ATM of pressure is equal to 33 feet (10 m) of depth of seawater or 14.7 pounds per square inch (psi) (101 kilopascals). The elevated pressure combined with exposure to 100% oxygen has many physiologic effects on the body. Many of these physiologic changes have been shown to improve wound healing in chronic wounds. This has been proven in many controlled studies. One of the most pronounced effects is the increase of oxygen concentration in the plasma. The normal oxygen concentration of plasma at sea level is 3 mL/L. At a pressure of 3 ATM breathing 100% oxygen, the plasma oxygen concentration approaches 60 mL/L. Studies have shown that this is enough to keep swine alive after all of their red blood cells have been removed and is sufficient to supply the resting oxygen requirement for most tissues. This also results in the delivery of higher oxygen concentrations to ischemic tissue. Another effect of hyperbaric oxygen therapy is decreasing surrounding edema and increasing neovascularity in ischemic tissue. Hyperbaric oxygen therapy can potentiate certain antibiotics such as aminoglycosides and quinolones. It can also be bacteriostatic and bacteriocidal at higher concentrations. Hyperbaric oxygen therapy neutralizes alpha exotoxins produced by bacteria such as Clostridium. It promotes neutrophil-mediated bacterial killing ability in hypoxic tissue. Hyperbaric oxygen therapy prevents the release of proteases and free radicals in certain injuries, thereby decreasing vasoconstriction, edema, and cellular damage.[1]