Multidrug-resistant Bacterial Infections Research Articles

Nucleus-Targeting Photosensitizers Enhance Neutrophil Extracellular Traps for Efficient Eradication of Multidrug-Resistant Bacterial Infections.

Neutrophil extracellular traps (NETs) are web-like complexes of DNA and proteins that are extruded by activated neutrophils and play critical roles as major components of the innate immune response against pathogen invasion. However, some microbes have developed strategies to evade NET attacks, leading to impaired immune defenses and persistent infections. In this study, an engineered neutrophil strategy for enhancing the antibacterial activity of NETs is developed. A nucleus-targeting photosensitizer (NCP) with strong reactive oxygen species production and a strong DNA-binding capacity is synthesized. NCP-loaded neutrophils are subsequently constructed via direct incubation of NCP with neutrophils, and the NCP is closely inserted into the nucleus DNA. Upon activation by bacteria-related toxins, NCP-coupled NETs can be released rapidly, actively trapping bacteria and providing a high local concentration of NCP around them. Both in vitro and in vivo results revealed that NCP-coupled NETs can effectively eradicate various multidrug-resistant bacteria and biofilms through photodynamic therapy, overcome bacterial immune evasion, and promote tissue recovery from severe wound infections. This design can significantly strengthen NET function, providing a non-antibiotic alternative platform for treating bacterial infectious diseases.

DRAMP 4.0: an open-access data repository dedicated to the clinical translation of antimicrobial peptides.

Antimicrobial peptides (AMPs) are potential candidates for treating multidrug-resistant bacterial infections, yet only a small number of them have progressed into clinical trials. The main challenges include the poor stability and hemolytic/cytotoxic properties of AMPs. Considering this, in the update of the Data Repository of Antimicrobial Peptides (DRAMP), a new annotation on serum and protease stability is added, and special efforts were made to update the hemolytic/cytotoxic information of AMPs. The DRAMP 4.0 currently holds 30 260 entries (8 001 newly added), consisting of 11 612 general entries, 17 886 patent entries, 96 clinical entries, 377 specific entries, 110 entries with stability data, and 179 expanded entries. A total of 2891 entries possess experimentally determined hemolytic activity information, while 2674 entries contain cytotoxicity data by experimental validation. The update also covers new annotations, statistics, categories, functions, and download links. DRAMP is available online at http://dramp.cpu-bioinfor.org/.

Enhanced Antibacterial, Anti-Inflammatory, and Antibiofilm Activities of Tryptophan-Substituted Peptides Derived from Cecropin A-Melittin Hybrid Peptide BP100

The emergence of multidrug-resistant pathogens necessitates the development of novel antimicrobial agents. BP100, a short α-helical antimicrobial peptide (AMP) derived from cecropin A and melittin, has shown promise as a potential therapeutic. To enhance its efficacy, we designed and synthesized 16 tryptophan-substituted BP100 analogs based on helical wheel projections. Among these, BP5, BP6, BP8, BP11, and BP13 exhibited 1.5- to 5.5-fold higher antibacterial activity and improved cell selectivity compared to BP100. These analogs demonstrated superior efficacy in suppressing pro-inflammatory cytokine release in LPS-stimulated RAW 264.7 cells and eradicating preformed biofilms of multidrug-resistant Pseudomonas aeruginosa (MDRPA). Additionally, these analogs showed greater resistance to physiological salts and serum compared to BP100. Mechanistic studies revealed that BP100 and its analogs exert their antibacterial effects through membrane disruption, depolarization, and permeabilization. Notably, these analogs showed synergistic antimicrobial activity with ciprofloxacin against MDRPA. Our findings suggest that these tryptophan-substituted BP100 analogs represent promising candidates for combating multidrug-resistant bacterial infections, offering a multifaceted approach through their antibacterial, anti-inflammatory, and antibiofilm activities.

The Use of Cefiderocol in Gram-Negative Bacterial Infections at International Medical Center, Jeddah, Saudi Arabia

Background/Objectives: The necessity for ground-breaking treatments for Gram-negative infections is evident. The World Health Organization, the Infectious Diseases Society of America, and the European Commission have highlighted the critical insufficiency of efficient antibiotics, urging pharmaceutical businesses to manufacture new antibiotics. Therefore, developing new antibiotics with broad efficacy against Gram-negative pathogens is essential. Thus, this research aimed to evaluate the safety and effectiveness of cefiderocol in treating multidrug-resistant Gram-negative bacterial infections at the International Medical Center (IMC), Jeddah, Saudi Arabia. Methods: A retrospective analysis was conducted on patients treated from January 2021 to February 2023. Thirteen case groups treated with cefiderocol were compared to twenty control groups treated with other antibiotics. Results: The results indicated no statistically significant differences in ICU stay, comorbidity indices, or mortality rates between the two groups. Cefiderocol showed high clinical and microbiological cure rates, despite the severity of the patients’ conditions. Carbapenem-resistant Klebsiella pneumoniae and difficult-to-treat resistance Pseudomonas aeruginosa were the most prevalent pathogens in the case and control group, respectively. Two patients treated with cefiderocol developed Clostridioides difficile infection, emphasizing the need for close monitoring of potential adverse effects. Conclusions: The results of this study support cefiderocol as a viable alternative for managing serious infections instigated by multidrug-resistant Gram-negative bacteria.

The Use of Ceftazidime–Avibactam in a Pediatric Intensive Care Unit—An Observational Prospective Study

Background/objectives: Infections caused by carbapenem-resistant Enterobacterales (CRE) are progressively increasing in Pediatric Intensive Care Units (PICUs). Its treatment is challenging due to the lack of pediatric trials. CRE infections are associated with significantly poor outcomes, but ceftazidime–avibactam (CAZ-AVI) has been reported to be successful in their treatment. This study aimed to describe the use and outcome of CAZ-AVI in a PICU. Results: Ten patients were included, with 12 episodes of clinical suspicion or confirmed multidrug-resistant (MDR) bacterial infections treated with CAZ-AVI for surgical prophylaxis, suspicion of sepsis, pneumonia, and surgical wound infection. Of these patients, 80% received empirical treatment because of previous MDR bacterial colonization, and 60% were administrated combination therapy with aztreonam for Metallo-β-Lactamases (MBL)strains. No bacteria were resistant to CAZ-AVI. The average duration of the treatment was 3 days when cultures turned negative and 7 days when MDR bacteria were isolated. Methods: This was an observational prospective study of children treated with CAZ-AVI in the PICU of a tertiary hospital in 2022. Epidemiological, clinical, microbiological, and outcome data were collected. Conclusions: The most frequent use of CAZ-AVI in our PICU was the short-term empirical treatment for patients with previous MDR bacterial colonization and clinical suspicion of bacteremia or sepsis. Furthermore, the combination of CAZ-AVI plus aztreonam could be more effective for CRE infections, especially type Ambler class B as MBL strains.

Antibiofilm and antivirulence efficacy of Pleurotus platypus methanolic extract against Staphylococcus aureus through ROS generation and cell membrane disruption

Multi-drug resistance is recognized as a significant worldwide public health concern in the current century. Biofilm formation further exacerbates bacterial resistance to antibacterial medications, host immunological responses, and phagocytosis, resulting in long-lasting chronic illnesses. Investigating natural resources is a very potent approach for developing alternative anti-infective medications to effectively control multi-drug resistant bacterial infections. In this study, a unique mushroom species namely Pleurotus platypus had been discovered from the Terai-Duars region of West Bengal, India. The myco-chemical profiling and preliminary chemical analysis of Pleurotus platypus methanolic extract determined the significant presence of metabolites belonging to several major chemical classes such as flavonoid, alkaloid, triterpenoid, polyphenol, benzoic acids, coumarin, flavone etc. Most intriguingly, the extract possessed effective antibacterial, antibiofilm and antivirulence properties against Staphylococcus aureus and Methicillin resistant Staphylococcus aureus, one of the most notable drug-resistant opportunistic and nosocomial pathogens. Mechanistically, the mushroom extract enhanced the production of Reactive Oxygen Species (ROS) inside the targeted bacteria, causing alterations in membrane potential, damage to the cellular membrane and further release of intracellular DNA, destined to cell death. Moreover, the methanolic extract reported the eradication of pre-existing biofilms from the urinary catheter surface, hinting towards its future application in the related field. To summarize, Pleurotus platypus methanolic extract could be an excellent alternative antibacterial and antibiofilm therapeutic candidate for the effective management of Staphylococcus infections with improved outcome.

Prevalence of carbapenem-resistant Enterobacterales (CRE) in Saudi Arabia: A systematic review and meta-analysis

Antimicrobial resistance is a significant public health issue. In addressing the threat of multidrug resistant bacterial infections, carbapenems have been used. The carbapenem-resistant Enterobacterales (CRE) are, however, rapidly expanding worldwide. Since the issue of CRE is also a problem in Saudi Arabia, the current meta-analysis was performed to comprehensively evaluate the resistance rates to the main carbapenem antibiotics and determine the actual prevalence of CRE in the country. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was followed. Different web databases including PubMed, Scopus, Web of Science, and ScienceDirect were searched for relevant records. Data were extracted, and summary estimates for resistance to carbapenems were calculated using DerSimonian-Laird method of meta-analysis and the random-effects model. From a total of 787 retrieved records, 69 studies were found fully eligible and were included in the final analyses. More than 50 % of all the studies were conducted after 2010, and the most frequently examined members of the Enterobacterales were Escherichia coli and Klebsiella pneumoniae. The pooled prevalence estimate for imipenem resistance was 6.6 % (95 % CI: 4.7–9.2), 9.1 % (95 % CI: 6.7–12.3) for meropenem, and 18.6 % (95 % CI: 11.9–27.9) for ertapenem. High heterogeneity (I2 > 97 %, p < 0.001) was observed for all the estimates. Compared to other regions of the country, there was higher resistance rates in the Al-Qassim and Al-Jouf provinces. Additionally, resistance to ertapenem was as high as 34.2 % in the most recent study period (2021–2024). Proteus spp was the most prevalent CRE (26.2 %). This review highlights an increasing rate of carbapenem resistance among Enterobacterales, emphasizing the need for collaborative efforts to implement strict infection control and prevention measures. Consistent surveillance is indispensable for safeguarding public health, guiding clinical decisions, and strengthening efforts to tackle the challenges of antibiotic resistance.

Rapidly in situ forming antibiotic-free injectable hydrogel wound dressing for eradicating drug-resistant bacterial infections in human skin organoids

The rising prevalence of global antibiotic resistance evokes the urgent requirement to explore the alternative antimicrobial candidates. It is of great significance to overcome these serious threats of multidrug-resistant bacterial infections and difficult-to-heal cutaneous wounds to human health. Herein, we proposed a rapidly in situ forming innovative antibiotic-free hydrogel dressing with excellent biocompatibility, easy injectability, strong tissue adhesion and superior antibacterial activity against drug-resistant bacteria. An octa-armed poly(ethylene glycol) amine (Octa-PEG-NH2) was quickly crosslinked with a green industrial microbicide tetrakis (hydroxymethyl) phosphonium chloride (THPC) to form an antibacterial hydrogel (OPTH) by simple mixing without any other initiators or crosslinkers. A significant broad-spectrum antibacterial efficacy was demonstrated against Gram-positive Staphylococcus aureus (S. aureus), Gram-negative Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA). Significantly, benefiting from its flexible injectability and reliable tissue adhesion, the excellent antibacterial performances were further evidenced by employing human-induced pluripotent stem cell (iPSC)-derived skin organoids in a 3D culture system and rat animal wound models in vivo with MRSA infection, thus allowing for reepithelization promotion and wound healing. Collectively, the findings not only propose a facile gelatinization strategy for readily accessible antibiotic-free hydrogel dressings for effective MRSA therapy but also hold great clinical translation potential in obliterating multi-pathogenic bacteria and accelerating wound healing.

Self-assembly antimicrobial peptide for treatment of multidrug-resistant bacterial infection

The wide-spreading of multidrug resistance poses a significant threat to human and animal health. Although antimicrobial peptides (AMPs) show great potential application, their instability has severely limited their clinical application. Here, self-assembled AMPs composed of multiple modules based on the principle of associating natural marine peptide N6 with ß-sheet-forming peptide were designed. It is noteworthy that one of the designed peptides, FFN could self-assemble into nanoparticles at 35.46 µM and achieve a dynamic transformation from nanoparticles to nanofibers in the presence of bacteria, resulting in a significant increase in stability in trypsin and tissues by 1.72–57.5 times compared to that of N6. Additionally, FFN exhibits a broad spectrum of antibacterial activity against multidrug-resistant (MDR) gram-positive (G+) and gram-negative (G−) bacteria with Minimum inhibitory concentrations (MICs) as low as 2 µM by membrane destruction and complemented by nanofiber capture. In vivo mouse mastitis infection model further confirmed the therapeutic potential and promising biosafety of the self-assembled peptide FFN, which can effectively alleviate mastitis caused by MDR Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), and eliminate pathogenic bacteria. In conclusion, the design of peptide-based nanomaterials presents a novel approach for the delivery and clinical translation of AMPs, promoting their application in medicine and animal husbandry.Graphical

Phages ZC01 and ZC03 require type-IV pilus for Pseudomonas aeruginosa infection and have a potential for therapeutic applications.

There has been a growing interest in bacteriophages as therapeutic agents to treat multidrug-resistant bacterial infections. The present work aimed at expanding the microbiological and molecular characterization of lytic phages ZC01 and ZC03 and investigating their efficacy in the control of Pseudomonas aeruginosa infection in an invertebrate animal model. These two phages were previously isolated from composting using P. aeruginosa strain PA14 as the enrichment host and had their genomes sequenced. ZC01 and ZC03 present, respectively, siphovirus and podovirus morphotypes. ZC01 was recently classified into the genus Abidjanvirus, while ZC03 belongs to Zicotriavirus genus of the Schitoviridae N4-like viruses. Through proteomics analysis, we identified virion structural proteins of ZC01 and ZC03, including a large virion-associated RNA polymerase that is characteristic of N4-like viruses, some hypothetical proteins whose annotation should be changed to virion structural proteins and a putative peptidoglycan hydrolase. Phages ZC01 and ZC03 exhibit a limited yet distinct host range, with moderate to high efficiency of plating (EOP) values observed for a few P. aeruginosa clinical isolates. Phage susceptibility assays in PA14 mutant strains point to the type-IV pilus (T4P) as the primary receptor for phages ZC01 and ZC03, and the major pilin (PilAPA14) is the T4P component recognized by these phages. Moreover, both phages significantly increase survival of Galleria mellonella larvae infected with PA14 strain. Taken together, these results underpin the therapeutic potential of these phages to treat infections by P. aeruginosa and lay the groundwork for a more detailed investigation of phage-bacteria-specific recognition mechanisms.IMPORTANCEPhage therapy is gaining increasing interest in cases of difficult-to-treat bacterial human infections, such as carbapenem-resistant Pseudomonas aeruginosa. In this work, we investigated the molecular mechanism underlying the interaction of the lytic phages ZC01 and ZC03 with the highly virulent P. aeruginosa PA14 strain and their efficacy to treat PA14 infection in Galleria mellonella larvae, a commonly used invertebrate model for phage therapy. We depicted the protein composition of ZC01 and ZC03 viral particles and identified pilin A, the major component of type-4 pilus, as the receptor recognized by these phages. Our findings indicate that phages ZC01 and ZC03 may be further used for developing therapies to treat multidrug-resistant P. aeruginosa infections.

Computational prediction of a phage cocktail active against multidrug-resistant bacteria

Background Antibiotic misuse and overuse have contributed to the emergence of multi-drug resistant (MDR) bacteria, posing a serious public health problem across the globe. Phage cocktails, which combine multiple phages, provide an efficient method to combat multidrug-resistant bacterial infections. This study integrated a computational pipeline to design a phage cocktail against the bacterial strains Acinetobacter baumannii AB0057, Klebsiella pneumoniae subsp. pneumoniae HS11286, and Pseudomonas aeruginosa UCBPP-PA14. Methods The whole genome sequences of selected multidrug-resistant bacteria were accessed. Prophage sequences were identified from them which could be expressed to produce viable lytic phages against MDR bacterial strains, thereby reducing the severity of infection. Prophages were annotated for open reading frames (ORFs), putative promoters, virulence factors, transcriptional terminators, ribosomal RNAs, and transfer RNAs. A dot plot was also generated to investigate similar phages and phylogenetic analysis was performed. Results A total of 11 prophages were predicted from the bacterial genomes. About 472 open reading frames were predicted along with 3 transfer RNAs. Additionally, the presence of 754 putative promoters and 281 transcription terminator sequences was also detected. Comparative genomic and phylogenetic analyses provided insight into the diversity, relatedness, and lytic potential of the phages. The final designed phage cocktail consisted of five selected prophages including Acinetobacter baumannii prophages (2759376-2809756) and (3311844-3364667), and Klebsiella pneumoniae prophages (1288317-1338719), (1778306-1808606), and (2280703-2325555). Conclusion The phage cocktail designed in this study might be useful against MDR Acinetobacter baumannii and Klebsiella pneumoniae infections, especially where conventional antibiotics fail. Sequence similarity analysis suggested that the phage cocktail may also be effective against other carbapenemase-producing K. pneumoniae strains.

Dispensing of antibiotics in community pharmacies before, during, and after the COVID-19 pandemic

Abstract Background Antibiotic resistance threatens our capability to successfully treat bacteriological infections, becoming a major threat to public health. Therefore, measures must be taken to minimize de incidence of multi-drug resistant bacterial infections. Antimicrobial Stewardship is a systemic healthcare approach devised to foster, enhance, oversee, and assess the judicious application of antimicrobials, aiming to safeguard their efficacy in the future, whilst advocating and safeguarding public health. In the initial phase, a correct diagnosis of antimicrobial utilization is pivotal for the proper implementation of an Antimicrobial Stewardship Program. Methods A cross-sectional study encompassing the Alentejo region, Portugal, with a specific focus on central Alentejo, was conducted to analyze the dispensing of antimicrobials in community pharmacies, alongside the examination of the prescribing locations, before, during, and after the COVID-19 pandemic, from 2019 to 2023. Results The number of antibiotic packages dispensed decreased, as expected, during the COVID-19 pandemic, but returned to pre-pandemic levels after its conclusion. In several prescribing locations, the proportion of cephalosporins and quinolones exceeded the maximum expected value. Conclusions The implementation of an appropriate Antimicrobial Stewardship Program in this region is necessary to ensure the correct prescription of antimicrobials, decreasing the risk that antibiotic resistance pose to public health. Emphasis on the application of the Clinical Practice Guidelines issued by the Portuguese Directorate-General of Health regarding the proper approach to bacterial infections should be intensified so that all prescribing locations exhibit proportions of cephalosporins and quinolones below the maximum expected value. Key messages • Antimicrobial resistance poses a threat to public health. • Stewardship is crucial for appropriately safeguarding public health by reducing antimicrobial resistance emergence.

Iron Single-Atom Nanozyme with Inflammation-Suppressing for Inhibiting Multidrug-Resistant Bacterial Infection and Facilitating Wound Healing.

Infection with drug-resistant bacteria and the formation of biofilms are the main factors contributing to wound healing insufficiency. Antibacterial agents with enzyme-like properties have exhibited considerable potential for efficient eradication of drug-resistant microorganisms due to their superior sensitivities and minimal side effects. In this work, we prepared a kind of Fe-centered single-atom nanozyme (Fe-SAzyme) with high biocompatibility and stability via a facile one-pot hydrothermal method, which was suitable for the treatment of wounds infected with drug-resistant bacteria. The Fe-SAzyme exhibited remarkable peroxidase-like catalytic activities, catalyzing the conversion of hydrogen peroxide (H2O2) to highly toxic hydroxyl radicals (•OH), which could not only damage bacterial cells but also inhibit, disrupt, and eradicate the formation of bacterial biofilms. Thus, Fe-SAzyme demonstrated a broad-spectrum antibacterial performance capable of effectively eliminating multidrug-resistant bacteria. The coexistence of ferrous (Fe2+) and ferric (Fe3+) ions in Fe-SAzyme conferred the nanozyme with anti-inflammatory activity, effectively suppressing excessive inflammation. Meanwhile, Fe-SAzyme could significantly downregulate inflammatory cytokines tumor necrosis factor-α and interleukin-1β and upregulate growth factors VEGF and epidermal growth factor, which can prevent bacterial infection, mitigate inflammation, promote fibroblast proliferation, and improve wound closure. Thus, Fe-SAzyme had shown favorable therapeutic efficiency in promoting bacteria-infected wound healing. This study provides Fe-SAzyme as a promising candidate for the development of new strategies to treat multidrug-resistant bacterial infections.

Comparison of efficacy and safety between elacycline and polymyxin for complicated intra-abdominal infections caused by multidrug-resistant bacteria

Objective: To compare the efficacy and safety of eravacycline and polymyxin drugs in the treatment of multidrug-resistant complicated intra-abdominal infections(cIAI). Methods: The cIAI patients diagnosed or highly suspected of multidrug resistant bacterial infection who received eravacycline treatment at Sir Run Run Shaw Hospital and Shulan (Hangzhou) Hospital from June to August 2023 were prospectively included as the elacycline group. The cIAI patients with cIAI caused by multidrug resistant bacteria who received treatment with polymyxin (B or E) from January 2021 to August 2023 were retrospectively collected. The acute physiology and chronic health scores and age were matched with those of the elacrinid group, and they were included in the polymyxin group. The study mainly analyzed the clinical efficacy, microbial clearance rate, comprehensive efficacy, and safety of the two groups at the end of treatment and discharge. Results: A total of 72 patients with cIAI were included in the study, including 53 males and 19 females, aged (56.0±15.4) years. Among them, there were 28 cases in the eravacycline group and 44 cases in the polymyxin group. There was no statistically significant differences in the baseline, the proportion of patients who used combined drugs, the strains, the infection sites and infection conditions of patients between the two groups(all P>0.05).The clinical efficacy rate at the end of treatment [89.3% (25/28) vs 56.8%(25/44), P=0.004] and discharge [(88.5%(23/26) vs 63.6%,(28/44), P=0.024], microbial clearance rate at the end of treatment [(88.9% (24/27) vs 47.6%(20/42), P=0.001] and discharge [(91.3%(21/23) vs 59.5%(25/42), P=0.007], and overall recovery rate at the end of treatment [(89.3%(25/28) vs 52.3%(23/44), P=0.001] and discharge [(88.5%(23/26) vs 63.6%(28/44), P=0.024] in the erythromycin group were higher than those in the polymyxin drug group. In terms of safety, only 2 cases of mild vasculitis were observed in the eravacycline group. Conclusions: Combined regimens based on eravacycline showed better clinical effect in the treatment of cIAI caused by multidrug-resistant bacteria. The clinical effective rate, microbial clearance rate and comprehensive efficacy were significantly higher than those of polymyxin drugs at the end of treatment and discharge with good safety.

The heterogeneous syndrome of non-infectious causes of persistent fever in neutropenic patients with hematologic malignancy: another opportunity for stewardship?

Although occult fungal, viral and multidrug-resistant bacterial infections can cause persistent fever in neutropenic patients with hematologic cancer, a variety of non-infectious entities should be considered in case-by-case basis in the context of negative diagnostic workup for infection.

Phage-Based Therapy in Combination with Antibiotics: A Promising Alternative against Multidrug-Resistant Gram-Negative Pathogens.

The continued rise in antimicrobial resistance poses a serious threat to public health worldwide. The use of phages that can have bactericidal activity without disrupting the normal flora represents a promising alternative treatment method. This practice has been successfully applied for decades, mainly in Eastern Europe, and has recently been used as an emergency therapy for compassionate care in the United States. Here, we provide a comprehensive review of the pre-clinical and clinical applications of phage therapy concerning three major Gram-negative pathogens: Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The advantages and the challenges of expanding the usage of phages as an alternative or adjunctive treatment for antimicrobial-resistant bacterial infections are discussed. We emphasize the virologic complexities of using the highly adaptable phage populations as molecular tools, along with antibiotic chemical compounds, to effectively combat rapidly coevolving pathogenic bacteria in the host microenvironment. Pre-clinical studies, isolated clinical reports and a few randomized clinical trials have shown that bacteriophages can be effective in treating multidrug-resistant bacterial infections. The ability of some phages to revert the resistance against antibiotics, and possibly also against the human complement and other phages, appears to be a great advantage of phage therapy despite the inevitable emergence of phage-resistant strains. Bacteriophages (or specific phage-derived products) can enhance antimicrobial efficacy by reducing bacterial virulence via the alteration of basic bacterial structures, primarily of the cellular wall and membrane. Although several issues remain open regarding their effective clinical application, it appears that phage-based therapeutics in combination with antibiotics can provide an effective solution to the spread of antimicrobial resistance.

Imidazoles and Quaternary Ammonium Compounds as Effective Therapies against (Multidrug-Resistant) Bacterial Wound Infections.

The rise and spread of antimicrobial resistance complicates the treatment of bacterial wound pathogens, further increasing the need for newer, effective therapies. Azoles such as miconazole have shown promise as antibacterial compounds; however, they are currently only used as antifungals. Previous research has shown that combining azoles with quaternary ammonium compounds yields synergistic activity against fungal pathogens, but the effect on bacterial pathogens has not been studied yet. In this study, the focus was on finding active synergistic combinations of imidazoles and quaternary ammonium compounds against (multidrug-resistant) bacterial pathogens through checkerboard assays. Experimental evolution in liquid culture was used to evaluate the possible emergence of resistance against the most active synergistic combination. Several promising synergistic combinations were identified against an array of Gram-positive pathogens: miconazole/domiphen bromide, ketoconazole/domiphen bromide, clotrimazole/domiphen bromide, fluconazole/domiphen bromide and miconazole/benzalkonium chloride. Especially, miconazole with domiphen bromide exhibits potential, as it has activity at a low concentration against a broad range of pathogens and shows an absence of strong resistance development over 11 cycles of evolution. This study provides valuable insight into the possible combinations of imidazoles and quaternary ammonium compounds that could be repurposed for (topical) wound treatment. Miconazole with domiphen bromide shows the highest application potential as a possible future wound therapy. However, further research is needed into the mode of action of these compounds and their efficacy and toxicity in vivo.

A chitosan-modified tea tree oil self-nanoemulsion improves antibacterial effects in vivo and in vitro and promotes wound healing by influencing metabolic processes against multidrug-resistant bacterial infections

Infectious diseases, especially multidrug-resistant bacterial infections, have caused crises and majorly disrupted public health and economic stability worldwide. Many natural essential oils, especially tea tree oil, have potential to treat multidrug-resistant bacteria, such as H. pylori and P. aeruginosa. However, there are some problems need to be solved, such as poor stability upon light or oxygen exposure. Therefore, it is urgent to develop the ideal formation to tackle these difficulties. Herein, we reported the novel chitosan-modified self-nanoemulsion (TNE) encapsulating natural essential tea tree oil with strong antibacterial and stability characterize. In this study, we found that this self-nanoemulsion (size: 212 nm, PDI: 0.124, zeta potential: −20.5 mV, 6 % tea tree oil) not only had physical properties, good stability and tissue safety, but also had better antibacterial synergism (2–8 times) than that of water suspension against various multidrug-resistant bacterial (such as H. pylori, MRSA and P. aeruginosa). Additionally, TNE showed high antibacterial effectiveness in vivo, reduced inflammation, promoted ulcer healing after H. pylori infection and accelerated wound healing after P. aeruginosa infection. Importantly, this novel self-nanoemulsion can induce 274 protein down-regulated and 251 protein up-regulated, and disrupt H. pylori metabolic processes (glyoxylate, dicarboxylic acid, glutamate and tryptophan metabolism) and reduced its viability, leading to significant synergistic antibacterial effects. TNE is a potential treatment for skin wounds or ulcers caused by multidrug-resistant bacterial infections.

Adjuvants restore colistin sensitivity in mouse models of highly colistin-resistant isolates, limiting bacterial proliferation and dissemination.

Antimicrobial resistance (AMR) has led to a marked reduction in the effectiveness of many antibiotics, representing a substantial and escalating concern for global health. Particularly alarming is resistance in Gram-negative bacteria due to the scarcity of therapeutic options for treating infections caused by these pathogens. This challenge is further compounded by the rising incidence of resistance to colistin, an antibiotic traditionally considered a last resort for the treatment of multi-drug resistant (MDR) Gram-negative bacterial infections. In this study, we demonstrate that adjuvants restore colistin sensitivity in vivo. We previously reported that the salicylanilide kinase inhibitor IMD-0354, which was originally developed to inhibit the human kinase IKKβ in the NFκB pathway, is a potent colistin adjuvant. Subsequent analog synthesis using an amide isostere approach led to the creation of a series of novel benzimidazole compounds with enhanced colistin adjuvant activity. Herein, we demonstrate that both IMD-0354 and a lead benzimidazole effectively restore colistin susceptibility in mouse models of highly colistin-resistant Klebsiella pneumoniae and Acinetobacter baumannii-induced peritonitis. These novel adjuvants show low toxicity in vivo, significantly reduce bacterial load, and prevent dissemination that could otherwise result in systemic infection.

In vitro evaluation of Morinda lucida root extracts against multi-drug resistant bacterial pathogens isolated from diabetic foot ulcers

Background: The continuous rise in microbial resistance to orthodox antimicrobial drugs has led to the search for alternative sources with proven efficacy to solve the challenges of antimicrobial resistance (AMR). The preferred alternatives are plant sources, and this has led to the evaluation of constituents and potency of medicinal plants to provide scientific justification for their use. Methodology: The root of Morinda lucida plant was dug up from the ground, washed clean, and cut into smaller pieces and dried. The root was then ground into fine powder and extracted with water (aqueous), methanol, ethyl acetate and n-hexane. Multi-drug resistant (MDR) Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Pseudomonas aeruginosa were isolated from wound swab samples collected from patients with diabetic foot ulcers using conventional cultures, biochemical identification, and antimicrobial susceptibility tests. The phytochemical and proximate contents of the extracts were assessed by standard technique. The in vitro antimicrobial activities of the extracts were determined at a concentration of 200mg/ml of the extract using the agar well diffusion technique. The minimum inhibitory and bactericidal concentrations were determined by serial doubling dilution. The methanol extract time-kill assay was performed to determine the time of kill of the bactericidal concentration. Results: The phytochemical analysis showed that M. lucida root contains essential secondary metabolites such as flavonoids, alkaloids, tannin, saponin, glucosides, anthraquinone and quinine. The methanol and aqueous extracts showed higher in vitro antibacterial activity, producing the highest zone of inhibition of 27mm against S. aureus but a lower activity of 18mm with n-hexane extract against all isolates except S. aureus. The MIC ranges from 3.125mg/ ml and 25mg/ml. The time-kill assay of methanol extract at 2x and 3x MIC showed that bactericidal activity occurred within 0-8 hours of incubation, indicating high activity. Conclusion: The antibacterial potency of M. lucida root extract and the phytochemical components from this study shows that it can serve as a source of alternative antimicrobial agent that may be effective in the treatment MDR bacterial infections.