Multidrug-resistant Infections Research Articles

Nurses' satisfaction with an educational web application to prevent transmission of multidrug-resistant organisms.

Multidrug-resistant organism infections are a serious health problem globally, and can result in patient mortality and morbidity. In this descriptive study, we produced the first web application for transmission prevention specific to the situation based on nursing experience, knowledge, and practice guidelines and to evaluate web application satisfaction among Thai nurses. The sample comprised 282 Thai registered nurses experienced in caring for patients with multidrug-resistant organisms in a tertiary hospital. A demographic form and knowledge test were completed anonymously online. Data were analyzed using descriptive statistics. The application emphasized crucial topics for which participants had low preliminary knowledge and included tutorial sessions, pictures, video clips, drills, and a post-test. The application was piloted with a random sample of 30 nurses, and an instrument tested their satisfaction with this. Results revealed that preliminary knowledge scores for preventing transmission were moderate, and participants were highly satisfied with the application. Findings suggest the application is suitable for Thai nurses and could be applied to nursing practice elsewhere. However, further testing is recommended before implementing it into nursing practice.

Emergence of Virulent Extensively Drug-Resistant Vancomycin-Resistant Enterococci Among Diarrheic Pet Animals: A Possible Public Health Threat on the Move.

Background: Vancomycin-resistant enterococci (VRE) have become an increasing public health concern in the past few decades, being associated with serious multidrug-resistant (MDR) infections. This study was conducted to investigate the role of diarrheic pet animals as potential reservoirs for virulent extensively drug-resistant (XDR) VRE and their threat on human health. Materials and Methods: Rectal swabs were collected from 153 diarrheic pet animals (80 dogs and 73 cats). The collected swabs were cultured on CHROMagarTMVRE for the isolation of vancomycin-resistant Enterococcus faecalis and Enterococcus faecium, and then suspected colonies were identified as enterococci after Gram staining, conventional biochemical tests, and molecular techniques. VRE were basically identified using the disk diffusion method; however, molecular identification of vanA and vanB genes was carried out among confirmed VRE isolates. Moreover, three virulence genes (cytolysin A, cylA; enterococcal surface protein, esp; and hyaluronidase, hyl) were investigated in VRE isolates. Thereafter, VRE strains that harbored virulence genes were tested for antimicrobial susceptibility. Results: Eighteen out of 153 animals (11.8%) were positive for VRE, which were obtained from 15% and 8.2% of the examined dogs and cats, respectively. None of the obtained isolates carried the vanA gene, whereas the vanB gene was detected in E. faecalis (4/10) with a prevalence rate (40%). Of the obtained VRE isolates, five possessed esp and/or cylA, while all strains were negative for the hyl gene. Furthermore, four virulent VRE isolates exhibited an XDR pattern, and one isolate was MDR. Conclusion: Diarrheic pet animals could represent a potential zoonotic reservoir for virulent XDR vancomycin-resistant E. faecalis, which may have serious public health implications.

A retrospective study of the predictors of mortality among patients in intensive care units at North West-Bank hospitals in Palestine

ABSTRACT Objectives The intensive care unit (ICU) mortality rate remains high especially in developing countries regardless of the advances in critical management. There is a lack of studies about mortality causes in hospitals and particularly ICUs in Palestine. This study evaluated the demographic and clinical characteristics of critically ill patients and determined the predictors of mortality among patients in the ICU. Methods A retrospective study assessed all patients who stayed in ICU for more than 24 hours from January 2017 to January 2019. Data were collected from the patient’s files. Patient characteristics (background, clinical variables, and comorbidities) were recorded. Results The study included 227 eligible ICU patients. The cases’ mean age was 55.5 (SD ± 18.2) years. The overall ICU mortality rate was 31.7%. The following factors were associated with high adjusted mortality odds: admission from inside the hospital (adjusted odds ratio (aOR), 2.1, 95%CI: 1.1-3.9, p < 0.05), creatinine level ≥2 mg/dl on admission (aOR, 2.7, 95%CI: 1.3-5.8, p < 0.01), hematology malignancy patients (aOR, 3.4, 95%CI: 1.6-6.7, p = 0.001), immune-compromised (aOR, 2.5, 95%CI: 1.3-4.7, p < 0.01), septic shock (aOR, 27.1, 95%CI: 7.9-88.3, p < 0.001), hospital-acquired infections (aOR: 13.4, 95%CI: 4.1-57.1, p < 0.001), and patients with multiple-source infection (aOR: 16.3, 95%CI: 6.4-57.1, p < 0.001). Also, high SOFA and APACHE scores predicted morality (p < 0.001). Conclusion The mortality rate among ICU patients was high. It was higher among those admitted from the hospital wards, septic shock, hospital-acquired infection, multiple infection sources, and multi-drug resistance infections. Thus, strategies should be developed to enhance ICU environment and provide sufficient resources to minimize the effects of these predictors.

Evaluation of stem cell therapies in companion animal disease models: A concise review (2015-2023).

Companion animals in veterinary medicine develop multiple naturally occurring diseases analogous to human conditions. We previously reported a comprehensive review on the feasibility, safety, and biologic activity of using novel stem cell therapies to treat a variety of inflammatory conditions in dogs and cats (2008-2015) [1]. The purpose of this review is to provide an updated summary of current studies in companion animal disease models that have evaluated stem cell therapeutics that are relevant to human disease. Here we have reviewed the literature from 2015 to 2023 for publications on stem cell therapies that have been evaluated in companion animals, including dogs, cats, and horses. The review excluded case reports or studies performed in experimentally induced models of disease, studies involving cancer, or studies in purpose-bred laboratory species such as rodents. We identified 45 manuscripts meeting these criteria, an increase from 19 that were described in the previous review [1]. The majority of studies were performed in dogs (n=28), with additional studies in horses (n=9) and cats (n=8). Disease models included those related to musculoskeletal disease (osteoarthritis, tendon/ligament injury), neurologic disease (canine cognitive dysfunction, intervertebral disc disease, spinal cord injury) gingival/dental disease (gingivostomatitis), dermatologic disease (atopic dermatitis), chronic multi-drug resistant infections, ophthalmic disease (keratoconjunctivitis sicca, eosinophilic keratitis, immune mediated keratitis), cardiopulmonary disease (asthma, degenerative valve disease, dilated cardiomyopathy), gastrointestinal disease (inflammatory bowel disease, chronic enteropathy) and renal disease (chronic kidney disease). The majority of studies reported beneficial responses to stem cell treatment, with the exception of those related to more chronic processes such as spinal cord injury and chronic kidney disease. However, it should also be noted that 22 studies were open-label, baseline-controlled trials and only 12 studies were randomized and controlled, making overall study interpretation difficult. As noted in the previous review, improved regulatory oversight and consistency in manufacturing of stem cell therapies is needed. Enhanced understanding of the temporal course of disease processes using advanced -omics approaches may further inform mechanisms of action and help define appropriate timing of interventions. Future directions of stem cell-based therapies could include use of stem-cell derived extracellular vesicles, or cell conditioning approaches to direct cells to specific pathways that are tailored to individual disease processes and stages of illness.

Risk factors and economic burden for community-acquired multidrug-resistant organism-associated urinary tract infections: A retrospective analysis.

The spread of multidrug-resistant organisms (MDROs) has resulted in a corresponding increase in the incidence of urinary tract infections (UTIs). The risk factors and hospitalization burden for community-acquired MDRO-associated UTIs are discussed herein. This retrospective study included 278 patients with community-based MDRO-associated UTIs from January 2020 to January 2022. The MDRO (n = 139) and non-MDRO groups (n = 139) were separated based on drug susceptibility results. Community-based MDRO-associated UTIs mainly occurred in the elderly and frail patients with a history of invasive urinary tract procedures. The MDRO group imposed a greater economic burden compared to the non-MDRO group. Independent risk factors for community-based MDRO-associated UTIs were as follows: white blood cell (WBC) count > 10.0 × 109/L (OR = 2.316, 95% CI = 1.316-3.252; P = .018); ≥3 kinds of urinary tract obstructive diseases (OR = 1.720, 95% CI = 1.004-2.947; P = .048); use of 3rd generation cephalosporins (OR = 2.316, 95% CI = 1.316-4.076; P = .004); and a history of invasive urologic procedures (OR = 2.652, 95% CI = 1.567-4.487; P < .001). Days of hospitalization, antibiotic use, and bladder catheter use were significantly greater in the MDRO group than the non-MDRO group (P < .05).

Mechanisms of Gelofusine Protection against Polymyxin B-associated Renal Injury.

Polymyxins are a last-resort treatment option for multidrug-resistant Gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated. Here, we report the use of a cell culture model to provide insights into the mechanisms of renal protection. Murine epithelial proximal tubular cells were exposed to polymyxin B. Cell viability, polymyxin B uptake, mitochondrial superoxide production, nuclear morphology, and apoptosis activation were evaluated with or without concomitant gelofusine. A megalin-knockout cell line was used as an uptake inhibition control. Methionine was included in selected experiments as an antioxidant control. A polymyxin B concentration-dependent reduction in cell viability was observed. Increased viability was observed in megalin-knockout cells following comparable polymyxin B exposures. Compared to polymyxin B exposure alone, concomitant gelofusine and methionine significantly increased cell viability, reduced mitochondrial superoxide production, and improved nuclear morphology. Gelofusine, but not methionine, significantly reduced polymyxin B uptake and ratio of Bax/Bcl-2 protein (a biomarker of intrinsic apoptosis). Gelofusine and methionine were more effective at reducing renal cell injury in combination than either agent alone. The mechanisms of renal protection by gelofusine involve decreasing cellular drug uptake, reducing subsequent oxidative stress and apoptosis activation. These findings would be valuable for translational research into clinical strategies to attenuate drug-associated acute kidney injury.

Photochemical Strategies toward Precision Targeting against Multidrug-Resistant Bacterial Infections.

Infectious diseases pose a serious threat and a substantial economic burden on global human and public health security, especially with the frequent emergence of multidrug-resistant (MDR) bacteria in clinical settings. In response to this urgent need, various photobased anti-infectious therapies have been reported lately. This Review explores and discusses several photochemical targeted antibacterial therapeutic strategies for addressing bacterial infections regardless of their antibiotic susceptibility. In contrast to conventional photobased therapies, these approaches facilitate precise targeting of pathogenic bacteria and/or infectious microenvironments, effectively minimizing toxicity to mammalian cells and surrounding healthy tissues. The highlighted therapies include photodynamic therapy, photocatalytic therapy, photothermal therapy, endogenous pigments-based photobleaching therapy, and polyphenols-based photo-oxidation therapy. This comprehensive exploration aims to offer updated information to facilitate the development of effective, convenient, safe, and alternative strategies to counter the growing threat of MDR bacteria in the future.

Genome analyses of colistin-resistant high-risk blaNDM-5 producing Klebsiella pneumoniae ST147 and Pseudomonas aeruginosa ST235 and ST357 in clinical settings

BackgroundColistin is a last-resort antibiotic used in extreme cases of multi-drug resistant (MDR) Gram-negative bacterial infections. Colistin resistance has increased in recent years and often goes undetected due to the inefficiency of predominantly used standard antibiotic susceptibility tests (AST). To address this challenge, we aimed to detect the prevalence of colistin resistance strains through both Vitek®2 and broth micro-dilution. We investigated 1748 blood, tracheal aspirate, and pleural fluid samples from the Intensive Care Unit (ICU), Neonatal Intensive Care Unit (NICU), and Tuberculosis and Respiratory Disease centre (TBRD) in an India hospital. Whole-genome sequencing (WGS) of extremely drug-resitant (XDR) and pan-drug resistant (PDR) strains revealed the resistance mechanisms through the Resistance Gene Identifier (RGI.v6.0.0) and Snippy.v4.6.0. Abricate.v1.0.1, PlasmidFinder.v2.1, MobileElementFinder.v1.0.3 etc. detected virulence factors, and mobile genetic elements associated to uncover the pathogenecity and the role of horizontal gene transfer (HGT).ResultsThis study reveals compelling insights into colistin resistance among global high-risk clinical isolates: Klebsiella pneumoniae ST147 (16/20), Pseudomonas aeruginosa ST235 (3/20), and ST357 (1/20). Vitek®2 found 6 colistin-resistant strains (minimum inhibitory concentrations, MIC = 4 μg/mL), while broth microdilution identified 48 (MIC = 32–128 μg/mL), adhering to CLSI guidelines. Despite the absence of mobile colistin resistance (mcr) genes, mechanisms underlying colistin resistance included mgrB deletion, phosphoethanolamine transferases arnT, eptB, ompA, and mutations in pmrB (T246A, R256G) and eptA (V50L, A135P, I138V, C27F) in K. pneumoniae. P. aeruginosa harbored phosphoethanolamine transferases basS/pmrb, basR, arnA, cprR, cprS, alongside pmrB (G362S), and parS (H398R) mutations. Both strains carried diverse clinically relevant antimicrobial resistance genes (ARGs), including plasmid-mediated blaNDM-5 (K. pneumoniae ST147) and chromosomally mediated blaNDM-1 (P. aeruginosa ST357).ConclusionThe global surge in MDR, XDR and PDR bacteria necessitates last-resort antibiotics such as colistin. However, escalating resistance, particularly to colistin, presents a critical challenge. Inefficient colistin resistance detection methods, including Vitek2, alongside limited surveillance resources, accentuate the need for improved strategies. Whole-genome sequencing revealed alarming colistin resistance among K. pneumoniae and P. aeruginosa in an Indian hospital. The identification of XDR and PDR strains underscores urgency for enhanced surveillance and infection control. SNP analysis elucidated resistance mechanisms, highlighting the complexity of combatting resistance.

Risk Factors for Therapeutic Failure and One-Year Mortality in Patients with Intramedullary Nail-Associated Infection after Trochanteric and Subtrochanteric Hip Fracture Repair.

Despite the implications of trochanteric and subtrochanteric intramedullary (IM) nail infection for patients with hip fracture, little is known about risk factors for therapeutic failure and mortality in this population. We performed a retrospective observational analysis including patients diagnosed with trochanteric and subtrochanteric IM nail infection at a Spanish academic hospital during a 10-year period, with a minimum follow-up of 22 months. Of 4044 trochanteric and subtrochanteric IM nail implants, we identified 35 cases of infection during the study period (0.87%), 17 of which were chronic infections. Patients with therapeutic failure (n = 10) presented a higher average Charlson Comorbidity Index (CCI) (5.40 vs. 4.21, p 0.015, CI 0.26-2.13) and higher rates of polymicrobial (OR 5.70, p 0.033, CI 1.14-28.33) and multidrug-resistant (OR 7.00, p 0.027, CI 1.24-39.57) infections. Upon multivariate analysis, polymicrobial infection and the presence of multidrug-resistant pathogens were identified as independent risk factors for therapeutic failure. Implant retention was associated with an increased risk of failure in chronic infection and was found to be an independent risk factor for overall one-year mortality in the multivariate analysis. Our study highlights the importance of broad-spectrum empirical antibiotics as initial treatment of trochanteric and subtrochanteric IM nail-associated infection while awaiting microbiological results. It also provides initial evidence for the importance of implant removal in chronic IM-nail infection.

A membrane-targeting magnolol derivative for the treatment of methicillin-resistant Staphylococcus aureus infections

Multidrug-resistant bacterial infections are a major global health challenge, especially the emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) urgently require alternative treatment options. Our study has identified that a magnolol derivative 6i as a promising agent with significant antibacterial activity against S. aureus and clinical MRSA isolates (MIC = 2–8 μg/mL), showing high membrane selectivity. Unlike traditional antibiotics, 6i demonstrated rapid bactericidal efficiency and a lower propensity for inducing bacterial resistance. Compound 6i also could inhibit biofilm formation and eradicate bacteria within biofilms. Mechanistic studies further revealed that 6i could target bacterial cell membranes, disrupting the integrity of the cell membrane and leading to increased DNA leakage, resulting in potent antibacterial effects. Meanwhile, 6i also showed good plasma stability and excellent biosafety. Notably, 6i displayed good in vivo antibacterial activity in a mouse skin abscess model of MRSA-16 infection, which was comparable to the positive control vancomycin. These findings indicated that the magnolol derivative 6i possessed the potential to be a novel anti-MRSA infection agent.

Multidrug resistance and urinary tract infection: A bibliometric analysis

Multidrug resistance and urinary tract infection: A bibliometric analysis

Advancements in nanoparticle-based therapies for multidrug-resistant candidiasis infections: a comprehensive review.

Candida auris, a rapidly emerging multidrug-resistant fungal pathogen, poses a global health threat, with cases reported in over 47 countries. Conventional detection methods struggle, and the increasing resistance of C. auris to antifungal agents has limited treatment options. Nanoparticle-based therapies, utilizing materials like silver, carbon, zinc oxide, titanium dioxide, polymer, and gold, show promise in effectively treating cutaneous candidiasis. This review explores recent advancements in nanoparticle-based therapies, emphasizing their potential to revolutionize antifungal therapy, particularly in combating C. auris infections. The discussion delves into mechanisms of action, combinations of nanomaterials, and their application against multidrug-resistant fungal pathogens, offering exciting prospects for improved clinical outcomes and reduced mortality rates. The aim is to inspire further research, ushering in a new era in the fight against multidrug-resistant fungal infections, paving the way for more effective and targeted therapeutic interventions.

Tracking success of interaction of green-synthesized Carbopol nanoemulgel (neomycin-decorated Ag/ZnO nanocomposite) with wound-based MDR bacteria

Abstract Multidrug-resistant wound infections are a global health threat and a leading cause of death, persisting despite available treatments due to antibiotic resistance, biofilms, and ineffective drug delivery systems. The aim of this study is to (i) formulate an innovative nano-drug delivery system (NDDS) based on a Carbopol nanoemulgel (NEG) co-loaded with neomycin-silver/zinc oxide nanocomposite (NC) that could fight clinical MDR and treat biofilm-forming wound pathogens through topical application, and (ii) assess its in vivo wound-healing potential. The silver/zinc oxide (Ag/ZnO) NC was synthesized by co-inoculating the metabolites of Aspergillus welwitschiae and Meyerozyma guilliermondii. The synthesized NC was then conjugated with neomycin and loaded into a Carbopol NEG for efficient topical delivery. The resulting Neo-Ag/ZnO NEG was characterized physicochemically (e.g., UV-visible [UV-Vis] spectrophotometry, field emission scanning electron microscopy, X-ray diffraction, and Fourier transform infrared [FTIR] spectroscopy), biologically (e.g., in vitro antimicrobial, antibiofilm, and hemolytic activities), and pharmacologically (e.g., drug content, ex vivo drug release behavior, and in vivo wound-healing potential). The physicochemical analysis confirmed the successful mycosynthesis of the Carbopol NEG-loaded Neo-Ag/ZnO NC. SEM depicted a crystalline polyhedral shape of the small NC (average particle size of 38 nm). FTIR studies showed a slight interaction with the drug and other bioactive moieties in the Carbopol NEG. The Neo content in the Carbopol NEG was as high as 98%, and a maximum release of 81% for Neo, Ag, and ZnO ions was noticed after 12 h. The NDDS appeared hemocompatible and displayed a minimal inhibition concentration of 0.002 µg/mL with the greatest antimicrobial potential against S. aureus (an inhibition zone of 46 mm) compared to other tested wound microbes (p &lt; 0.05). Statistically significant wound-healing activity was found for NDDS (p = 0.0001) in comparison to the control at a concentration of 100 mg/mL. The results showed that this newly developed Carbopol NEG-loaded neo-Ag/ZnO NC appeared promising for controlling resistant skin infections and boosting wound regeneration.

Colonization by Extended-Spectrum β-Lactamase-Producing Enterobacterales and Bacteremia in Hematopoietic Stem Cell Transplant Recipients.

Assessing the risk of multidrug-resistant colonization and infections is pivotal for optimizing empirical therapy in hematopoietic stem cell transplants (HSCTs). Limited data exist on extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) colonization in this population. This study aimed to assess whether ESBL-E colonization constitutes a risk factor for ESBL-E bloodstream infection (BSI) and to evaluate ESBL-E colonization in HSCT recipients. A retrospective analysis of ESBL-E colonization and BSI in HSCT patients was conducted from August 2019 to June 2022. Weekly swabs were collected and cultured on chromogenic selective media, with PCR identifying the β-lactamase genes. Pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing (WGS) assessed the colonizing strains' similarities. Of 222 evaluated HSCT patients, 59.45% were colonized by ESBL-E, with 48.4% at admission. The predominant β-lactamase genes were blaTEM (52%) and blaSHV (20%). PFGE analysis did not reveal predominant clusters in 26 E. coli and 15 K. pneumoniae strains. WGS identified ST16 and ST11 as the predominant sequence types among K. pneumoniae. Thirty-three patients developed thirty-five Enterobacterales-BSIs, with nine being third-generation cephalosporin-resistant. No association was found between ESBL-E colonization and ESBL-BSI (p = 0.087). Although the patients presented a high colonization rate of ESBL-E upon admission, no association between colonization and infection were found. Thus, it seems that ESBL screening is not a useful strategy to assess risk factors and guide therapy for ESBL-BSI in HSCT-patients.

Significance of Triazole in Medicinal Chemistry: Advancement in Drug Design, Reward and Biological Activity.

One of the triazole tautomers, 1,2,4-triazole derivatives, has a wide range of biological activities that suggest its potential therapeutic utility in medicinal chemistry. These actions include anti-inflammatory, anti-cancer, anti-bacterial, anti-tuberculosis, and anti-diabetic effects. The review highlights anti-inflammatory effect of 1,2,4-triazoles in relation to their ability to disrupt significant inflammatory mediators and pathways. We present in-silico data that illuminate the triazolescapacity to inhibit cell division, encourage apoptosis, and stop metastasis in a range of cancer models. This review looks at the bactericidal and bacteriostatic properties of 1,2,4-triazole derivatives, with a focus on their potential efficacy against multi-drug resistant bacterial infections and their usage in tuberculosis therapy. In order to better understand these substances' potential anti-diabetic benefits, this review also looks at how they affect glucose metabolism regulation and insulin responsiveness.Based oninformation provided, it can be concluded that 1,2,4-triazole derivatives are a promising class of diverse therapeutic agents with potential utility in a range of disorders. Their development and improvement might herald a new era of medical care that will be immensely advantageous to both patients and medical community as a whole.Additionally, this study encourages more research into these substances and their enhancement for use in pharmaceutical development.

Membrane Permeability Dominates over Electrostatic Interactions in Dictating Drug Transport in Osmotically Shocked Escherichia coli.

To combat surging multidrug-resistant Gram-negative bacterial infections, better strategies to improve the efficacy of existing drugs are critical. Because the dual membrane cell envelope is the first line of defense for these bacteria, it is crucial to understand the permeation properties of the drugs through it. Our recent study shows that isosmotic conditions prevent drug permeation inside Gram-negative bacteria, Escherichia coli, while hypoosmotic stress enhances the process. Here, we unravel the reason behind such differential drug penetration. Specifically, we dissect the roles of electrostatic screening and low membrane permeability in the penetration failure of drugs under osmotically balanced conditions. We compare the transport of a quaternary ammonium compound malachite green in the presence of an electrolyte (NaCl) and a wide variety of commonly used organic osmolytes, e.g., sucrose, proline, glycerol, sorbitol, and urea. These osmolytes of different membrane permeability (i.e., nonpermeable sucrose and NaCl, freely permeable urea and glycerol, and partially permeable proline and sorbitol) clarify the role of osmotic stress in cell envelope permeability. The results showcase that under balanced osmotic conditions, drug molecules fail to penetrate inside E. coli cells because of low membrane permeabilities and not because of electrostatic screening imposed by the osmolytes. Contribution of the electrostatic interactions, however, cannot be completely overruled as at osmotically imbalanced conditions, drug transport across the bacterial subcellular compartments is found to be dependent on the osmolytes used.

Photodynamic inactivation of E. coli with cationic imidazolyl-porphyrin photosensitizers and their synergic combination with antimicrobial cinnamaldehyde.

Bacterial infections are a global health concern, particularly due to the increasing resistance of bacteria to antibiotics. Multi-drug resistance (MDR) is a considerable challenge, and novel approaches are needed to treat bacterial infections. Photodynamic inactivation (PDI) of microorganisms is increasingly recognized as an effective method to inactivate a broad spectrum of bacteria and overcome resistance mechanisms. This study presents the synthesis of a new cationic 5,15-di-imidazolyl porphyrin derivative and the impact of n-octanol/water partition coefficient (logP) values of this class of photosensitizers on PDI efficacy of Escherichia coli. The derivative with logP = -0.5, IP-H-OH2+, achieved a remarkable 3 log CFU reduction of E. coli at 100nM with only 1.36J/cm2 light dose at 415nm, twice as effective as the second-best porphyrin IP-H-Me2+, of logP = -1.35. We relate the rapid uptake of IP-H-OH2+ by E. coli to improved PDI and the very low uptake of a fluorinated derivative, IP-H-CF32+, logP ≈ 1, to its poor performance. Combination of PDI with cinnamaldehyde, a major component of the cinnamon plant known to alter bacteria cell membranes, offered synergic inactivation of E. coli (7 log CFU reduction), using 50nM of IP-H-OH2+ and just 1.36J/cm2 light dose. The success of combining PDI with this natural compound broadens the scope of therapies for MDR infections that do not add drug resistance. In vivo studies on a mouse model of wound infection showed the potential of cationic 5,15-di-imidazolyl porphyrins to treat clinically relevant infected wounds.

Graphene Quantum Dots Nanoantibiotic-Sensitized TiO2- x Heterojunctions for Sonodynamic-Nanocatalytic Therapy of Multidrug-Resistant Bacterial Infections.

The exploration of sonodynamic therapy (SDT) as a possible replacement for antibiotics by creating reactive oxygen species (ROS) is suggested as a non-drug-resistant theranostic method. However, the low-efficiency ROS generation and complex tumor microenvironment which can deplete ROS and promote tumor growth will cause the compromised antibacterial efficacy of SDT. Herein, through an oxygen vacancy engineering strategy, TiO2- x microspheres with an abundance of Ti3+ are synthesized using a straightforward reductant co-assembly approach. The narrow bandgaps and Ti3+/Ti4+-mediated multiple-enzyme catalytic activities of the obtained TiO2- x microspheres make them suitable for use as sonosensitizers and nanozymes. When graphene quantum dot (GQD) nanoantibiotics are deposited on TiO2- x microspheres, the resulting GQD/TiO2- x shows an increased production of ROS, which can be ascribed to the accelerated separation of electron-hole pairs, as well as the peroxidase-like catalytic activity mediated by Ti3+, and the depletion of glutathione mediated by Ti4+. Moreover, the catalytic activities of TiO2- x microspheres are amplified by the heterojunctions-accelerated carrier transfer. In addition, GQDs can inhibit Topo I, displaying strong antibacterial activity and further enhancing the antibacterial activity. Collectively, the combination of GQD/TiO2- x-mediated SDT/NCT with nanoantibiotics can result in a synergistic effect, allowing for multimodal antibacterial treatment that effectively promotes wound healing.

Tailored Phototherapy Agent by Infection Site In Situ Activated Against Methicillin-Resistant S. aureus.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a promising treatment approach for multidrug resistant infections. PDT/PTT combination therapy can more efficiently eliminate pathogens without drug resistance. The key to improve the efficacy of photochemotherapy is the utilization efficiency of non-radiation energy of phototherapy agents. Herein, a facile phototherapy molecule (SCy-Le) with the enhancement of non-radiative energy transfer is designed by an acid stimulation under a single laser. Introduction of the protonated receptor into SCy-Le results in a distorted intramolecular charge in the infected acidic microenvironment, pH ≈ 5.5, which in turn, enhances light capture, reduces the singlet-triplet transition energies (ΔES1-T1), promotes electron system crossing, enhances capacity of reactive oxygen speciesgeneration, and causes a significant increase in temperature by improving vibrational relaxation. SCy-Le shows more than 99% bacterial killing rate against both methicillin-resistant Staphylococcus aureus and its biofilms in vitro and causes bacteria-induced wound healing in mice. This work will provide a new perspective for the design of phototherapy agents, and the emerging photochemotherapy will be a promising approach to combat the problem of antibiotic resistance.

Enhancing the stability and therapeutic potential of the antimicrobial peptide Feleucin-K3 against Multidrug-Resistant a. Baumannii through rational utilization of a D-amino acid substitution strategy

Antimicrobial peptides (AMPs), which have a low probability of developing resistance, are considered the most promising antimicrobial agents for combating antibiotic resistance. Feleucin-K3 is an amphiphilic cationic AMP that exhibits broad-spectrum antimicrobial activity. In our previous research, the first phenylalanine residue was identified as the critical position affecting its biological activity. Here, a series of Feleucin-K3 analogs containing hydrophobic D-amino acids were developed, leveraging the low sensitivity of proteases to unnatural amino acids and the regulatory effect of hydrophobicity on antimicrobial activity. Among them, K-1dF, which replaced the phenylalanine of Feleucin-K3 with its enantiomer (D-phenylalanine), exhibited potent antimicrobial activity with a therapeutic index of 46.97 and MICs between 4 to 8 μg/ml against both sensitive and multidrug-resistant Acinetobacter baumannii. The introduction of D-phenylalanine increased the salt tolerance and serum stability of Feleucin-K3. Moreover, K-1dF displayed a rapid bactericidal effect, a low propensity to develop resistance, and a synergistic effect when combined with antibiotics. More importantly, it exhibited considerable or superior efficacy to imipenem against pneumonia and skin abscess infection. In brief, the K-1dF obtained by simple and effective modification strategy has emerged as a promising candidate antimicrobial agent for tackling multidrug-resistant Acinetobacter baumannii infections.