Antibiotic-resistant Infections Research Articles

A potential therapeutic strategy of an innovative probiotic formulation toward topical treatment of diabetic ulcer: an in vivo study

BackgroundThe probiotic potential of Lacticacid bacteria has been studied in various medical complications, from gastrointestinal diseases to antibiotic resistance infections recently. Moreover, diabetic ulcer (DU) is known as one of the most significant global healthcare concerns, which comprehensively impacts the quality of life for these patients. Given that the conventional treatments of DUs have failed to prevent later complications completely, developing alternative therapies seems to be crucial.MethodsWe designed the stable oleogel-based formulation of viable probiotic cells, including Lactobacillus rhamnosus (L. rhamnosus), Lactobacillus casei (L. casei), Lactobacillus fermentum (L. fermentum), and Lactobacillus acidophilus (L. acidophilus) individually to investigate their effect on wound healing process as an in vivo study. The wound repair process was closely monitored regarding morphology, biochemical, and histopathological changes over two weeks and compared it with the effects of topical tetracycline as an antibiotic approach. Furthermore, the antibiofilm activity of probiotic bacteria was assessed against some common pathogens.ResultsThe findings indicated that all tested lactobacillus groups (excluded L. casei) included in the oleogel-based formulation revealed a high potential for repairing damaged skin due to the considerably more levels of hydroxyproline content of tissue samples along with the higher numerical density of mature fibroblasts cell and volume density of hair follicles, collagen fibrils, and neovascularization in comparison with antibiotic and control groups. L. acidophilus and L. rhamnosus showed the best potential of wound healing among all lactobacillus species, groups treated by tetracycline and control groups. Besides, L. rhamnosus showed a significant biofilm inhibition activity against tested pathogens.ConclusionsThis experiment demonstrated that the designed formulations containing probiotics, particularly L. acidophilus and L. rhamnosus, play a central role in manipulating diabetic wound healing. It could be suggested as an encouraging nominee for diabetic wound-healing alternative approaches, though further studies in detailed clinical trials are needed.

PH-responsive and nanoenzyme-loaded artificial nanocells relieved osteomyelitis efficiently by synergistic chemodynamic and cuproptosis therapy

Osteomyelitis is an osseous infectious disease that primarily affects children and the elderly with high morbidity and recurrence. The conventional treatments of osteomyelitis contain long-term and high-dose systemic antibiotics with debridements, which are not effective and lead to antibiotic resistance with serious side/adverse effects in many cases. Hence, developing novel antibiotic-free interventions against osteomyelitis (especially antibiotic-resistant bacterial infection) is urgent and anticipated. Here, a bone mesenchymal stem cell membrane-constructed nanocell (CFE@CM) was fabricated against osteomyelitis with the characteristics of acid-responsiveness, hydrogen peroxide self-supplying, enhanced chemodynamic therapeutic efficacy, bone marrow targeting and cuproptosis induction. Notably, mRNA sequencing was applied to unveil the underlying biological mechanisms and found that the biological processes related to copper ion binding, oxidative phosphorylation, peptide biosynthesis and metabolism, etc., were disturbed by CFE@CM in bacteria. This work provided an innovative antibiotic-free strategy against osteomyelitis through copper-enhanced Fenton reaction and distinct cuproptosis, promising to complement the current insufficient therapeutic regimen in clinic.

Analysis of antibiotic resistant infections associated with hirudotherapy

ObjectiveGiven rising concern regarding antibiotic resistance, our objective was to evaluate antibiotic-resistant infections following leech therapy and to characterize the use of prophylactic antibiotics. MethodsAll reports of adverse events involving hirudotherapy (product code “NRN”) were retrieved from the U.S. Food and Drug Administration MAUDE database between 2012 and 2021. Antibiotic resistance was defined by bacterial culture or infection after antibiotic administration. ResultsNineteen cases of antibiotic resistance involving hirudotherapy were identified. Only three cases of antibiotic resistance were discovered on routine testing and the remaining 16 cases were associated with patient injury. Positive blood cultures or fever were present in 26.3 % (n = 5) of cases. Cultures of the infection grew Aeromonas hydrophilia (n = 13; 68.4 %), Vibrio vulnificus (n = 3; 15.8 %), Pseudomonas aeruginosa (n = 2; 10.5 %), and Proteus vulgaris (n = 1; 5.3 %). There were nine (47.4 %) multi-drug resistant infections. Infection was most commonly resistant to fluoroquinolones (n = 9; 47.4 %), trimethoprim-sulfamethoxazole (n = 9; 47.4 %) and ertapenem (n = 4; 21.1 %). ConclusionAntibiotic-resistant infections involving hirudotherapy are frequently resistant to multiple drugs, including fluoroquinolones and trimethoprim-sulfamethoxazole. Resistance to ertapenem, a drug of last resort, was also documented. The findings presented in this study support growing literature that the trend in multi-drug resistance is more severe than previously reported.

Molecular Docking and Dynamic Simulation Studies of Bioactive Compounds from Traditional Medicinal Compounds Against Exfoliative Toxin B from Staphylococcus aureus

Background Staphylococcal scalded skin syndrome (SSSS) is a dermatological condition caused by Staphylococcus aureus, characterized by exfoliative toxin B, and its increasing resistance to conventional antibiotics necessitates the search for new therapeutic options. Aim The study aimed to investigate the potential of traditional medicinal compounds (TMCs) as potential pharmaceuticals against SSSS using molecular-level research. Introduction Staphylococcus aureus, commonly known as S. aureus, is the main cause of SSSS. These infections are a major concern for public health because they are becoming resistant to antibiotics. There is an urgent need for new medications to effectively fight against this infection. The main objective of this study was to assess the interaction between TMC compounds and S. aureus exfoliative toxins ETA and ETB utilizing computational approaches. Materials and Methods The investigation selected TMC compounds based on their potential to combat S. aureus infections. To predict binding affinities with the ETB toxin, molecular docking simulations were performed using AutoDock and AutoDock Vina. In order to evaluate the stability and interaction dynamics with the toxins, the most promising compound was subjected to a 100 ns molecular dynamics simulation. Stability was evaluated through various methods. Results Liquiritin showed the highest binding affinity, with a docking score of −7.6 kcal/mol. MD simulation confirmed the complex’s stability, and the binding free energy of −17.76 kcal/mol indicated potent inhibitory activity against S. aureus ETB. Conclusion Liquiritin, a TMC, effectively inhibits S. aureus toxins ETB, with promising potential for treating SSSS and antibiotic-resistant infections, requiring further research.

Synthetic mucus biomaterials synergize with antibiofilm agents to combat Pseudomonas aeruginosa biofilms.

Bacterial biofilms are often highly resistant to antimicrobials causing persistent infections which when not effectively managed can significantly worsen clinical outcomes. As such, alternatives to standard antibiotic therapies have been highly sought after to address difficult-to-treat biofilm-associated infections. We hypothesized a biomaterial-based approach using the innate functions of mucins to modulate bacterial surface attachment and virulence could provide a new therapeutic strategy against biofilms. Based on our testing in Pseudomonas aeruginosa biofilms, we found synthetic mucus biomaterials can inhibit biofilm formation and significantly reduce the thickness of mature biofilms. In addition, we evaluated if synthetic mucus biomaterials could work synergistically with DNase and/or α-amylase for enhanced biofilm dispersal. Combination treatment with these antibiofilm agents and synthetic mucus biomaterials resulted in up to 3 log reductions in viability of mature P. aeruginosa biofilms. Overall, this work provides a new bio-inspired, combinatorial approach to address biofilms and antibiotic-resistant bacterial infections.

Characterization and Anti-Biofilm Activity of Lytic Enterococcus Phage vB_Efs8_KEN04 against Clinical Isolates of Multidrug-Resistant Enterococcus faecalis in Kenya.

Enterococcus faecalis (E. faecalis) is a growing cause of nosocomial and antibiotic-resistant infections. Treating drug-resistant E. faecalis requires novel approaches. The use of bacteriophages (phages) against multidrug-resistant (MDR) bacteria has recently garnered global attention. Biofilms play a vital role in E. faecalis pathogenesis as they enhance antibiotic resistance. Phages eliminate biofilms by producing lytic enzymes, including depolymerases. In this study, Enterococcus phage vB_Efs8_KEN04, isolated from a sewage treatment plant in Nairobi, Kenya, was tested against clinical strains of MDR E. faecalis. This phage had a broad host range against 100% (26/26) of MDR E. faecalis clinical isolates and cross-species activity against Enterococcus faecium. It was able to withstand acidic and alkaline conditions, from pH 3 to 11, as well as temperatures between -80 °C and 37 °C. It could inhibit and disrupt the biofilms of MDR E. faecalis. Its linear double-stranded DNA genome of 142,402 bp contains 238 coding sequences with a G + C content and coding gene density of 36.01% and 91.46%, respectively. Genomic analyses showed that phage vB_Efs8_KEN04 belongs to the genus Kochikohdavirus in the family Herelleviridae. It lacked antimicrobial resistance, virulence, and lysogeny genes, and its stability, broad host range, and cross-species lysis indicate strong potential for the treatment of Enterococcus infections.

Quantifying Membrane Alterations with Tailored Fluorescent Dyes: A Rapid Antibiotic Resistance Profiling Methodology.

Accurate detection of bacterial antibiotic sensitivity is crucial for theranostics and the containment of antibiotic-resistant infections. However, the intricate task of detecting and quantifying the antibiotic-induced changes in the bacterial cytoplasmic membrane, and their correlation with other metabolic pathways leading to antibiotic resistance, poses significant challenges. Using a novel class of 4-aminophthalimide (4AP)-based fluorescent dyes with precisely tailored alkyl chains, namely 4AP-C9 and 4AP-C13, we quantify stress-mediated alterations in E. coli membranes. Leveraging the unique depth-dependent positioning and environment-sensitive fluorescence properties of these dyes, we detect antibiotic-induced membrane damage through single-cell imaging and monitoring the fluorescence peak maxima difference ratio (PMDR) of the dyes within the bacterial membrane, complemented by other methods. The correlation between the ROS-induced cytoplasmic membrane damage and the PMDR of dyes quantifies sensitivity against bactericidal antibiotics, which correlates to antibiotic-induced lipid peroxidation. Significantly, our findings largely extend to clinical isolates of E. coli and other ESKAPE pathogens like K. pneumoniae and Enterobacter subspecies. Our data reveal that 4AP-Cn probes can potentially act as precise scales to detect antibiotic-induced membrane damage ("thinning") occurring at a subnanometer scale through the quantification of dyes' PMDR, making them promising membrane dyes for rapid detection of bacterial antibiotic resistance, distinguishing sensitive and resistant infections with high specificity in a clinical setup.

Assessment of Antimicrobial Activity of Chitosan, ZnO, and Urtica dioica-ZnO NPs Against Staphylococcus aureus Isolated from Diabetic Ulcers.

Staphylococcus aureus (S. aureus) is considered as one of the challenging ulcer infections in diabetic patients especially those who have acquired antibiotic-resistant infections. Nanotechnology products have enormous potential to treat diseases including infectious diseases. As chitosan and zinc oxide (ZnO) nanoparticles (NPs) have harbored a high antimicrobial effect, this survey was aimed to synthesize chitosan, ZnO, and ZnO-Urtica. diocia (ZnO-U. diocia) NPs, and to assess their antimicrobial effects and their influence on virulencegenes expression in S. aureus isolates from diabetic ulcers. The antibacterial effect of NPs was detected by microdilution method. The most frequently components in U. diocia aqueous extract were linalool,4-thujanol, camphor, carvacrol, propanedioic acid, and di(butyl) phthalate. More than 95% of clinical S. aureus isolates were resistant to several antibiotics including erythromycin, cefoxitin, clindamycin, and ciprofloxacin. The most resistant isolates were S. aureus ATDS 52, ATDS 53, F5232, and F91. The lowest MIC and MBC by the NPs on the isolates was detected as 0.128 g/mL and 0.178g/mL, respectively. A significant decrease of 90% in the expression rates of lukED and RNAIII genes was reported for S. aureus isolates treated with the NPs. The synthetized ZnO-U. diocia and chitosan NPs can be proposed as a reliable and effective antimicrobial agent targeting diabetic ulcers infections caused by S. aureus because of its high effects on the bacterial growth and virulence genes expression.

Biguanide-Vancomycin Conjugates are Effective Broad-Spectrum Antibiotics against Actively Growing and Biofilm-Associated Gram-Positive and Gram-Negative ESKAPE Pathogens and Mycobacteria.

Strategies to increase the efficacy and/or expand the spectrum of activity of existing antibiotics provide a potentially fast path to clinically address the growing crisis of antibiotic-resistant infections. Here, we report the synthesis, antibacterial efficacy, and mechanistic activity of an unprecedented class of biguanide-antibiotic conjugates. Our lead biguanide-vancomycin conjugate, V-C6-Bg-PhCl (5e), induces highly effective cell killing with up to a 2 orders-of-magnitude improvement over its parent compound, vancomycin (V), against vancomycin-resistant enterococcus. V-C6-Bg-PhCl (5e) also exhibits improved activity against mycobacteria and each of the ESKAPE pathogens, including the Gram-negative organisms. Furthermore, we uncover broad-spectrum killing activity against biofilm-associated Gram-positive and Gram-negative bacteria as well as mycobacteria not observed for clinically used antibiotics such as oritavancin. Mode-of-action studies reveal that vancomycin-like cell wall synthesis inhibition with improved efficacy attributed to enhanced engagement at vancomycin binding sites through biguanide association with relevant cell-surface anions for Gram-positive and Gram-negative bacteria. Due to its potency, remarkably broad activity, and lack of acute mammalian cell toxicity, V-C6-Bg-PhCl (5e) is a promising candidate for treating antibiotic-resistant infections and notoriously difficult-to-treat slowly growing and antibiotic-tolerant bacteria associated with chronic and often incurable infections. More generally, this study offers a new strategy (biguanidinylation) to enhance antibiotic activity and facilitate clinical entry.

Manure application enriches phage-associated antimicrobial resistance and reconstructs ecological network of phage-bacteria in paddy soil

Antimicrobial resistance is an urgent threat to global health, causing serious antibiotic-resistant infections and deaths. The phages can serve as genetic reservoirs for bacterial adaptation, facilitating the horizontal transfer of antibiotic resistance genes (ARGs). However, how environmental perturbations impact the variation in viral ARGs via the phage-bacterial ecological network remains obscure. This study applied combined metagenomic and viromic sequencing without amplification bias to investigate the variations in the viral resistome and the ecological phage-bacterial networks in the paddy soils with different fertilizers. Results showed that manure application significantly changed the microbial community composition and increased the abundance of bacterial ARGs. The numbers of shared ARGs between paired virome and metagenome, as well as the diversity of host bacteria for phage-associated ARGs distinctly increased with manure amendment compared to chemical fertilizer treatment and non-fertilizer control. Elevated abundance of genes encoding stress and gene transfer-associated functions was observed in the manured soil viromes. Manure fertilization restructured the phage-bacteria ecological network with increased interactions potentially facilitating the dissemination of ARGs in the manure amended soils.

Bacteriophage vB_kpnS-Kpn15: Unveiling its potential triumph against extended-spectrum beta-lactamase-producing Klebsiella pneumoniae - Unraveling efficacy through innovative animal alternate models

Aim –To isolate bacteriophages targeting extended-spectrum beta-lactamase-producing K. pneumoniae and evaluate their effectiveness across diverse models, incorporating innovative alternatives in animal testing. Methods and resultsvB_kpnS-Kpn15 was isolated from sewage sample from Thane district. It produced a clear plaques on K. pneumoniae ATCC 700603. It has a flexible, non-contractile long tail and an icosahedral head and the Siphoviridae family of viruses in the order Caudovirales matched all of its structural criteria. Sequencing of vB_kpnS-Kpn15 revealed a 48,404 bp genome. The vB_KpnS-Kpn15 genome was found to contain 50 hypothetical proteins, of which 16 were found to possess different functions. The vB_KpnS-Kpn15 was also found to possess enzymes for its DNA synthesis. It was found to be lytic for the planktonic cells of K. pneumoniae and bactericidal for up to 48 h and potentially affected established K. pneumoniae biofilms. It demonstrated a broad host range and caused lytic zones on about 46 % of K. pneumoniae multi-drug resistant strains. In an in vitro wound and burn infection model, phage vB_kpnS-Kpn15 in combination with other phages resulted in successful cell proliferation and wound healing. Based on vB_kpnS-Kpn15's lytic properties, it can be incorporated in a bacteriophage cocktail to combat ESBL strains. ConclusionsThe phages isolated during this research are better candidates for phage therapy, and therefore provide new and exciting options for the successful control of antibiotic-resistant bacterial infections in the future. The utilization of animal alternative models in this study elucidates cellular proliferation and migration, underscoring its significance in screening novel drugs with potential applications in the treatment of wound and burn infections. Significance and impact of the researchThe findings of this research have implications for the creation of innovative, promising strategies to treat ESBL K. pneumoniae infections.

Biotechnological Production of the Recombinant Two-Component Lantibiotic Lichenicidin in a Bacterial Expression System

Objective: Lantibiotics are a family of bacterial antimicrobial peptides synthesized by ribosomes, that undergo post-translational modification to form lanthionine (Lan) and methyllanthionine (MeLan) residues. Lantibiotics are currently considered promising agents for combating antibiotic-resistant bacterial infections. This paper presents a biotechnological method for obtaining two components of the lantibiotic lichenicidin from Bacillus licheniformis B-511, Lchα and Lchβ. Such a system has the potential to facilitate the production of not only lichenicidin, but also other lantibiotics, including two-component ones, and also to enable the study of their biosynthesis and the activity and substrate specificity of modifying enzymes. Methods: The developed system is based on heterologous coexpression of the genes of Lchα and Lchβ precursors with the genes of their corresponding modifying enzymes in the cytoplasm of Escherichia coli BL21(DE3). Subsequent steps included immobilized metal affinity chromatography of the His-tagged hybrid peptide under denaturing conditions, cyanogen bromide cleavage in acidic medium, and final purification using reverse-phase HPLC. Results and Discussion: The system was employed for the expression and purification of lantibiotics, resulting in the successful isolation of the β-component of lichenicidin in high yield (approximately 4 mg/L of culture). This purified beta component exhibited structural and functional characteristics comparable to its natural counterpart, which was purified from the natural producer. However, the yield of the mature α-component of lichenicidin in such a system was significantly lower. Conclusions: The work presents a biotechnological method for obtaining recombinant two-component lantibiotic lichenicidin, which has proven to be particularly effective in the case of Lchβ. The developed method can also be applied to the production of other promising lantibiotics and their further research.

Analysis of therapeutic effect of silver-based dressings on chronic wound healing.

Chronic wounds are susceptible to bacterial infections and at high risk of developing antibiotic-resistant bacterial infections. Silver is an antimicrobial by targeting almost all types of bacteria in chronic wounds to reduce the bacterial load in the infected area and further facilitate the healing process. This study focused on exploring whether silver-based dressings were superior to non-silver dressings in the treatment of chronic wounds. PubMed, Web of Science and Embase were comprehensively searched from inception to March 2024 for randomized clinical trials and observational studies. The endpoints in terms of wound healing rate, complete healing time, reduction on wound surface area and wound infection rate were analysed using Review Manager 5.4 software. A total of 15 studies involving 5046 patients were eventually included. The results showed that compared with patients provided with non-silver dressings, patients provided with silver-based dressings had higher wound healing rate (OR: 1.43, 95% CI: 1.10-1.85, p = 0.008), shorter complete healing time (MD: -0.96, 95% CI: -1.08 ~ -0.85, p < 0.00001) and lower wound infection rate (OR: 0.56, 95% CI: 0.40-0.79, p = 0.001); no significant difference in the reduction on wound surface area (MD: 12.41, 95% CI: -19.59-44.40, p = 0.45) was found. These findings suggested that the silver-based dressings were able to enhance chronic wound healing rate, shorten the complete healing time and reduce wound infection rate, but had no significant improvement in the reduction on wound surface area. Large-scale and rigorous studies are required to confirm the beneficial effects of silver-based dressings on chronic wound healing.

Investigation and detection of multiple antibiotic-resistant pathogenic bacteria in municipal wastewater of Dhaka city

BackgroundWater pollution in densely populated urban areas, mainly from municipal wastewater, poses a significant threat. Pathogenic bacteria, such as Vibrio spp. and fecal coliform, endanger public health and the environment. Additionally, antibiotic-resistant bacteria in wastewater complicate treatment and heighten public health concerns.MethodsThe study sampled municipal wastewater from ten Dhaka neighborhoods, selecting treatment plants, sewage outlets, and various collection points using meticulous techniques for representative samples. Bacteriological and biochemical analyses were conducted using standardized methods. Antimicrobial susceptibility testing (AST) was performed with the disk diffusion method against 13 widely used antibiotics.ResultsAll sampled areas exhibited positive results for Vibrio spp., fecal coliform, E. coli, and Salmonella spp. Varying bacterial concentrations were observed, with the highest concentration of TVC, total vibrio spp., and total fecal coliform, total E. coli count, and total Salmonella spp. were found in Uttara (1.9 × 104 CFU/ml), Bangshal (1.8 × 102 CFU/ml), and Lalbag (2.1 × 103 CFU/ml), Mirpur (3.70 × 102 CFU/ml), and Lalbag (6 × 102 CFU/ml) respectively. AST results revealed significant resistance among all bacterial species to various antibiotics. Specifically, Vibrio spp. showed 100% resistance to cefuroxime, fecal coliform exhibited 90% resistance to cephradine, E. coli demonstrated 60% resistance to cephradine, and Salmonella spp. displayed 90% resistance to ampicillin.ConclusionThe study highlights the existence of multiple antibiotic-resistant bacteria in Dhaka's wastewater. Addressing antibiotic resistance is essential to manage the risks of multiple antibiotic-resistant infections and maintain antibiotic effectiveness. These implications are critical for various stakeholders, including public health officials, policymakers, environmentalists, and urban planners.

The pH-Insensitive Antimicrobial and Antibiofilm Activities of the Frog Skin Derived Peptide Esc(1-21): Promising Features for Novel Anti-Infective Drugs.

The number of antibiotic-resistant microbial infections is dramatically increasing, while the discovery of new antibiotics is significantly declining. Furthermore, the activity of antibiotics is negatively influenced by the ability of bacteria to form sessile communities, called biofilms, and by the microenvironment of the infection, characterized by an acidic pH, especially in the lungs of patients suffering from cystic fibrosis (CF). Antimicrobial peptides represent interesting alternatives to conventional antibiotics, and with expanding properties. Here, we explored the effects of an acidic pH on the antimicrobial and antibiofilm activities of the AMP Esc(1-21) and we found that it slightly lost activity (from 2- to 4-fold) against the planktonic form of a panel of Gram-negative bacteria, with respect to a ≥ 32-fold of traditional antibiotics. Furthermore, it retained its activity against the sessile form of these bacteria grown in media with a neutral pH, and showed similar or higher effectiveness against the biofilm form of bacteria grown in acidic media, simulating a CF-like acidic microenvironment, compared to physiological conditions.

Improving Chitosan/PVA Electrospun Nanofibers Antimicrobial Efficacy with Methylene Blue for Effective &lt;i&gt;E. Coli&lt;/i&gt; Inhibition Using Photodynamic Therapy

In view of the growing concern over the threat of antibiotic resistance and bacterial infections, this study evaluated the antimicrobial performance and characteristics of chitosan/polyvinyl alcohol (PVA) nanofibers incorporated with Methylene Blue (MB). Following the fabrication of chitosan/PVA nanofibers loaded with different MB concentrations via electrospinning, the samples were characterised through Field-emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared (FTIR) spectroscopy, and leaching tests. Finally, the antimicrobial inhibition level of the samples was assessed via the disc diffusion method. Based on the results, the MB-integrated chitosan/PVA nanofibers exhibited a nanoscale morphology, and the FTIR confirmed the presence of MB. The findings also established a positive correlation between the MB concentration and leaching intensity. Furthermore, the optimal antimicrobial efficacy against Escherichia coli was achieved by the chitosan/PVA/MB (5 wt.%) sample with a 2-min laser exposure, which recorded a significant inhibition zone of 8.65 mm. In conclusion, MB demonstrated potent antimicrobial properties against E. coli, suggesting its potential integration in electrospun nanofibers for combating bacterial infections via photodynamic therapy.

PyAMPA: a high-throughput prediction and optimization tool for antimicrobial peptides.

This paper introduces PyAMPA, a new bioinformatics platform designed for the discovery and optimization of antimicrobial peptides (AMPs). It addresses the urgent need for new antimicrobials due to the rise of antibiotic-resistant infections. PyAMPA, with its five predictive modules -AMPScreen, AMPValidate, AMPSolve, AMPMutate and AMPOptimize, enables high-throughput screening of proteomes to identify potential AMP motifs and optimize them for clinical use. Its unique approach, combining prediction, design, and optimization tools, makes PyAMPA a robust solution for developing new AMP-based therapies, offering a significant advance in combatting antibiotic resistance.

A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance

The lack of new drugs that are effective against antibiotic-resistant bacteria has caused increasing concern in global public health. Based on this study, we report development of a modified antimicrobial drug through structure-based drug design (SBDD) and modular synthesis. The optimal modified compound, F8, was identified, which demonstrated in vitro and in vivo broad-spectrum antibacterial activity against drug-resistant bacteria and effectively mitigated the development of resistance. F8 exhibits significant bactericidal activity against bacteria resistant to antibiotics such as methicillin, polymyxin B, florfenicol (FLO), doxycycline, ampicillin and sulfamethoxazole. In a mouse model of drug-resistant bacteremia, F8 was found to increase survival and significantly reduce bacterial load in infected mice. Multi-omics analysis (transcriptomics, proteomics, and metabolomics) have indicated that ornithine carbamoyl transferase (arcB) is a antimicrobial target of F8. Further molecular docking, Isothermal Titration Calorimetry (ITC), and Differential Scanning Fluorimetry (DSF) studies verified arcB as a effective target for F8. Finally, mechanistic studies suggest that F8 competitively binds to arcB, disrupting the bacterial cell membrane and inducing a certain degree of oxidative damage. Here, we report F8 as a promising candidate drug for the development of antibiotic formulations to combat antibiotic-resistant bacteria-associated infections.

Pseudomonas aeruginosa quorum sensing and biofilm attenuation by a di-hydroxy derivative of piperlongumine (PL-18)

Bacterial communication, Quorum Sensing (QS), is a target against virulence and prevention of antibiotic-resistant infections. 16 derivatives of Piperlongumine (PL), an amide alkaloid from Piper longum L., were screened for QS inhibition. PL-18 had the best QSI activity. PL-18 inhibited the lasR-lasI, rhlR-rhlI, and pqs QS systems of Pseudomonas aeruginosa. PL-18 inhibited pyocyanin and rhamnolipids that are QS-controlled virulence elements. Iron is an essential element for pathogenicity, biofilm formation and resilience in harsh environments, its uptake was inhibited by PL-18. Pl-18 significantly reduced the biofilm biovolume including in established biofilms. PL-18-coated silicon tubes significantly inhibited biofilm formation. The transcriptome study of treated P. aeruginosa showed that PL-18 indeed reduced the expression of QS and iron homeostasis related genes, and up regulated sulfur metabolism related genes. Altogether, PL-18 inhibits QS, virulence, iron uptake, and biofilm formation. Thus, PL-18 should be further developed against bacterial infection, antibiotic resistance, and biofilm formation.

Antimicrobial Effect of Passiflora foetida Leaf Extract

Antimicrobial resistance (AMR) is a critical global health concern under the present clinical scenario due to the overuse and misuse of antibiotics in both medical and agricultural sectors. Passiflora foetida, commonly known as wild maracuja or stinking passion flower belongs to the Passifloraceae family and is native to tropical and subtropical regions of Asia, Africa, Australia, and America. In this study, we aimed to explore the potential antimicrobial efficacy of Passiflora foetida leaf extract against both MDR bacteria and American Type Culture Collection (ATCC) strains for possible combating microbial infections in the future. The MIC value of Passiflora foetida extract varied between 5-10 mg/ml in different ATCC and MDR bacteria studied in this experiment. Passiflora foetida is also well known in traditional medicine indicating a degree of safety and efficacy, although modern scientific validation is necessary to support its therapeutic applications. Future research should focus on identifying the specific bioactive agent responsible for its antimicrobial effects, optimizing extraction methods to maximize bioavailability, and evaluating its safety and efficacy in animal models and clinical trials. Understanding the antimicrobial properties of Passiflora foetida is crucial for developing effective therapeutic strategies against antibiotic-resistant infections. By harnessing the natural antimicrobial potential of this plant, researchers may uncover new treatment options to combat AMR and improve patient outcomes. The findings of this study indicated its possible use as a topical application at present till further study with refined extract may reveal its application in vivo in different diseases with MDR microorganisms.