Multidrug-resistant Pathogens Research Articles

Comprehensive Exploration of Bromophenol Derivatives: Promising Antibacterial Agents against SA and MRSA.

The incidence of treatment failure due to multidrug-resistant pathogens elevated over the years; the rate is much higher than new antibiotic drug discovery. Therefore, bromophenol derivatives as potential antibacterial agents on Staphylococcus aureus and MRSA were explored in this research via integrating chemistry, microbiology, and pharmacology to address significant knowledge gaps pertaining to the antibacterial activity of bromophenols based on their functional groups. Surprisingly, a simple molecule, 3-bromo-2,6-dihydroxyacetophenone (2), exhibited good anti-S. aureus activity and even MRSA, a drug-resistant strain. In addition, compound 2 also inhibited a common resistant pathway of pathogens, biofilm formation of S. aureus and MRSA. Moreover, the therapeutic index of 2 is up to 598, which can be viewed as highly selective and having low toxicity to human HEK-293 cells. Although these compounds displayed less effectiveness for the Gram-negative bacterium, Pseudomonas aeruginosa, they still manifested some effects on the virulence properties of P. aeruginosa, such as biofilm formation, pyocyanin production, and swarming motility. In silico analyses of the structure-activity relationship as well as ADMET properties were discussed in the end. This study shed some light on the antibacterial activities of bromophenols.

BWC0977, a broad-spectrum antibacterial clinical candidate to treat multidrug resistant infections

The global crisis of antimicrobial resistance (AMR) necessitates the development of broad-spectrum antibacterial drugs effective against multi-drug resistant (MDR) pathogens. BWC0977, a Novel Bacterial Topoisomerase Inhibitor (NBTI) selectively inhibits bacterial DNA replication via inhibition of DNA gyrase and topoisomerase IV. BWC0977 exhibited a minimum inhibitory concentration (MIC90) of 0.03–2 µg/mL against a global panel of MDR Gram-negative bacteria including Enterobacterales and non-fermenters, Gram-positive bacteria, anaerobes and biothreat pathogens. BWC0977 retains activity against isolates resistant to fluoroquinolones (FQs), carbapenems and colistin and demonstrates efficacy against multiple pathogens in two rodent species with significantly higher drug levels in the epithelial lining fluid of infected lungs. In healthy volunteers, single-ascending doses of BWC0977 administered intravenously (https://clinicaltrials.gov/study/NCT05088421) was found to be safe, well tolerated (primary endpoint) and achieved dose-proportional exposures (secondary endpoint) consistent with modelled data from preclinical studies. Here, we show that BWC0977 has the potential to treat a range of critical-care infections including MDR bacterial pneumonias.

VIM-1-producing Enterobacter asburiae with mobile colistin resistance genes from wastewaters

BackgroundWastewaters are considered as important players in the spread of antimicrobial resistance, thus affecting the health of humans and animals. Here, we focused on wastewaters as a possible source of carbapenemase-producing Enterobacterales for the environment.MethodsA total of 180 presumptive coliforms from hospital and municipal wastewaters, and a river in the Czech Republic were obtained by selective cultivation on meropenem-supplemented media and tested for presence of carbapenemase-encoding genes by PCR. Strains carrying genes of interest were characterized by testing antimicrobial susceptibility, carbapenemase production and combination of short- and long- read whole-genome sequencing. The phylogenetic tree including publicly available genomes of Enterobacter asburiae was conducted using Prokka, Roary and RAxML.ResultsThree VIM-producing Enterobacter asburiae isolates, members of the Enterobacter cloacae complex, were detected from hospital and municipal wastewaters, and the river. The blaVIM−1 gene was located within a class 1 integron that was carried by different F-type plasmids and one non-typeable plasmid. Furthermore, one of the isolates carried plasmid-borne colistin-resistance gene mcr-10, while in another isolate chromosomally located mcr-9 without colistin resistance phenotype was detected. In addition, the analysis of 685 publicly available E. asburiae genomes showed they frequently carry carbapenemase genes, highlighting the importance of this species in the emergence of resistance to last-line antibiotics.ConclusionOur findings pointed out the important contribution of hospital and community wastewaters in transmission of multi-drug resistant pathogens.

Bdellovibrio bacteriovorus Therapy, an Emerging Alternative to Antibiotics

: The increase in multi-drug resistant (MDR) pathogens and the decline in the number of new antibiotics in the production pipeline pose a serious threat to our ability to treat infectious diseases. In this new landscape, once treatable diseases are now potentially life-threatening. This impending danger requires that urgent attention should be given to developing alternative strategies for combating MDR bacteria. A novel alternative is the use of predatory bacteria, B. bacteriovorus spp, that naturally prey on Gram-negative bacteria, including MDR Enterobacteriaceae. B. bacteriovorus has been shown to be nonpathogenic in animal models and on human cell lines, supporting its feasibility to be used to treat infections in animals and possibly humans. This document reviews various aspects of B. bacteriovorus biology, including its unique life cycle, "predatory toolbox", prey range, and recent research advances exploring B. bacteriovorus as an antimicrobial agent, stepping towards its use in human therapy. We also discuss the advantages and limitations of using B. bacteriovorus therapy and the strategies to overcome these limitations.

Silver secnidazole nano-hybrid emulsion-based probiotics as a novel antifungal formula against multidrug-resistant vaginal pathogens.

This study presents a novel approach to manage vaginal infections due to Candidiasis, utilizing a novel silver secnidazole nano-hybrid emulsion (Ag-Secn-NHE)-based probiotics and free Ag-Secn-NHE. Ag-Secn-NHE was prepared by simple homogenization‒ultrasonication technique and validated by using a ultraviolet‒visible scan, dynamic light scattering, transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy, and zeta potential. Saccharomyces cerevisiae (RCMB 002Y001) is the most effective probiotic-producing organism that demonstrates significant effects when combined with Ag-Secn-NHE. Ag-Secn-NHE-based probiotics showed significant antifungal effect compared to free Ag-Secn-NHE, silver nitrate, silver nanoparticles, secnidazole, secnidazole nanoemulsion, and commercial vaginal wash against multidrug-resistant vaginal pathogens. The highest inhibitory effect was achieved with Ag-Secn-NHE-based probiotic against Candida auris, Candida albicans, and Cryptococcus neoformans with minimal inhibitory concentration (MIC) 0.625±0.002, 0.00625:1.25±0.012 and 0.00625:1.25±0.032mg/mL, respectively, in comparison with Ag-Secn-NHE that show MIC at 0.00625:1.25±0.612, 0.0125:2.5±0.812, and 0.0125:2.5±0.112mg/mL (Ag:Secn). Ag-Secn-NHE-based- probiotic show minimum fungicidal concentration (MFC) at range from 2.5 to 20mg/mL, wherever free Ag-Secn-NHE show MFC range from 5 to >20mg/mL. Additionally, Ag-Secn-NHE-based probiotics have 75% inhibition of biofilm formation against C. auris and 60% inhibition of biofilm formation against both Cryptococcus neoformans and C. albicans in comparison with free Ag-Secn-NHE. Time-kill curves showed that the antifungal effect of Ag-Secn-NHE-based probiotics was fungistatic at 2MIC value after 4h and after 16h for Ag-Secn-NHE. TEM photographs showed that C. auris cells treated with Ag-Secn-NHE-based probiotic formula revealed severe deformations and distored ultrastructural changes. furthermore, results indicated that the Gamma radiation up to 15kGy increases production of Ag-Secn-NHE in comparison with non-irradiated one.

Antibiofilm activity of truncated Staphylococcus aureus phenol soluble modulin α2 (SaΔ1Δ2PSMα2) against Candida auris in vitro and in an animal model of catheter-associated infection

Candida auris has emerged as a major multidrug-resistant nosocomial pathogen. The organism exhibits a persistent colonising phenotype, and causes recalcitrant infections often strongly linked to biofilm formation. Alternate strategies are urgently needed to combat this yeast and its biofilm-associated phenotype. This work aimed to evaluate the efficacy of select staphylococcal phenol soluble modulins (PSMs), namely, a truncated version of Staphylococcus aureus PSMα2 shortened by two amino acids at the N-terminal (SaΔ1Δ2PSMα2) and Staphylococcus epidermidis PSMδ against C. auris in vitro and in vivo. The antifungal and antibiofilm activity was tested by broth microdilution and XTT dye reduction assay. Combination effect with antifungal drugs was determined by fractional inhibitory concentration test. The efficacy of combination therapy using SaΔ1Δ2PSMα2 with amphotericin B or caspofungin was evaluated in murine model of C. auris catheter-associated infection. Based on antifungal activity, antibiofilm activity and cytotoxicity data, SaΔ1Δ2PSMα2 exhibited promising activity against C. auris biofilms. Nearly 50 % inhibition in biofilm formation was noted with 0.5–2 μM of the peptide against multiple clinical and C. auris colonizing isolates. It was synergistic with amphotericin B (ΣFIC = 0.281) and caspofungin (ΣFIC = 0.047) in vitro, and improved the activity of voriconazole in voriconazole-resistant C. auris. Combination therapy using amphotericin B or caspofungin (1 μg/ml) with SaΔ1Δ2PSMα2 resulted in 99.5 % reduction in C. auris biofilm in murine model, even when the peptide was used at a concentration that was neither fungicidal nor antibiofilm (0.125 μM; ≈0.26 μg/ml). The study provides insight into the potential utility of SaΔ1Δ2PSMα2-antifungal drug combination against C. auris biofilm-associated infections.

Evaluation of the Antibacterial Potential of Two Short Linear Peptides YI12 and FK13 against Multidrug-Resistant Bacteria.

The accelerating spread of antibiotic resistance has significantly weakened the clinical efficacy of existing antibiotics, posing a severe threat to public health. There is an urgent need to develop novel antimicrobial alternatives that can bypass the mechanisms of antibiotic resistance and effectively kill multidrug-resistant (MDR) pathogens. Antimicrobial peptides (AMPs) are one of the most promising candidates to treat MDR pathogenic infections since they display broad-spectrum antimicrobial activities and are less prone to achieve drug resistance. In this study, we investigated the antibacterial capability and mechanisms of two machine learning-driven linear peptide compounds termed YI12 and FK13. We reveal that YI12 and FK13 exhibit broad-spectrum antibacterial properties against clinically significant bacterial pathogens, inducing no or minimal hemolysis in mammalian red blood cells. We further ascertain that YI12 and FK13 are resilient to heat and acid-base conditions, and exhibit susceptibility to hydrolytic enzymes and divalent cations under physiological conditions. Initial mechanistic investigations reveal that YI12 and FK13 compromise bacterial membrane integrity, leading to membrane potential dissipation and excessive reactive oxygen species (ROS) generation. Collectively, our findings highlight the prospective utility of these two cationic amphiphilic peptides as broad-spectrum antibacterial agents.

Phagemid-based capsid system for CRISPR-Cas13a antimicrobials targeting methicillin-resistant Staphylococcus aureus

In response to the escalating antibiotic resistance in multidrug-resistant pathogens, we propose an innovative phagemid-based capsid system to generate CRISPR-Cas13a-loaded antibacterial capsids (AB-capsids) for targeted therapy against multidrug-resistant Staphylococcus aureus. Our optimized phagemid system maximizes AB-capsid yield and purity, showing a positive correlation with phagemid copy number. Notably, an 8.65-fold increase in copy number results in a 2.54-fold rise in AB-capsid generation. Phagemids carrying terL-terS-rinA-rinB (prophage-encoded packaging site genes) consistently exhibit high packaging efficiency, and the generation of AB-capsids using lysogenized hosts with terL-terS deletion resulted in comparatively lower level of wild-type phage contamination, with minimal compromise on AB-capsid yield. These generated AB-capsids selectively eliminate S. aureus strains carrying the target gene while sparing non-target strains. In conclusion, our phagemid-based capsid system stands as a promising avenue for developing sequence-specific bactericidal agents, offering a streamlined approach to combat antibiotic-resistant pathogens within the constraints of efficient production and targeted efficacy.

Pharmacokinetics and pharmacodynamics of bacteriophage therapy: a review with a focus on multidrug-resistant Gram-negative bacterial infections.

SUMMARYDespite the early recognition of their therapeutic potential and the current escalation of multidrug-resistant (MDR) pathogens, the adoption of bacteriophages into mainstream clinical practice is hindered by unfamiliarity with their basic pharmacokinetic (PK) and pharmacodynamic (PD) properties, among others. Given the self-replicative nature of bacteriophages in the presence of host bacteria, the adsorption rate, and the clearance by the host's immunity, their PK/PD characteristics cannot be estimated by conventional approaches, and thus, the introduction of new considerations is required. Furthermore, the multitude of different bacteriophage types, preparations, and treatment schedules impedes drawing general conclusions on their in vivo PK/PD features. Additionally, the drawback of acquired bacteriophage resistance of MDR pathogens with clinical and environmental implications should be taken into consideration. Here, we provide an overview of the current state of the field of PK and PD of bacteriophage therapy with a focus on its application against MDR Gram-negative infections, highlighting the potential knowledge gaps and the challenges in translation from the bench to the bedside. After reviewing the in vitro PKs and PDs of bacteriophages against the four major MDR Gram-negative pathogens, Klebsiella pneumoniae, Acinetobacter baumannii complex, Pseudomonas aeruginosa, and Escherichia coli, specific data on in vivo PKs (tissue distribution, route of administration, and basic PK parameters in animals and humans) and PDs (survival and reduction of bacterial burden in relation to the route of administration, timing of therapy, dosing regimens, and resistance) are summarized. Currently available data merit close scrutiny, and optimization of bacteriophage therapy in the context of a better understanding of the underlying PK/PD principles is urgent to improve its therapeutic effect and to minimize the occurrence of bacteriophage resistance.

Valnemulin restores colistin sensitivity against multidrug-resistant gram-negative pathogens

Colistin is one of the last-resort antibiotics in treating infections caused by multidrug-resistant (MDR) pathogens. Unfortunately, the emergence of colistin-resistant gram-negative strains limit its clinical application. Here, we identify an FDA-approved drug, valnemulin (Val), exhibit a synergistic effect with colistin in eradicating both colistin-resistant and colistin-susceptible gram-negative pathogens both in vitro and in the mouse infection model. Furthermore, Val acts synergistically with colistin in eliminating intracellular bacteria in vitro. Functional studies and transcriptional analysis confirm that the combinational use of Val and colistin could cause membrane permeabilization, proton motive force dissipation, reduction in intracellular ATP level, and suppression in bacterial motility, which result in bacterial membrane disruption and finally cell death. Our findings reveal the potential of Val as a colistin adjuvant to combat MDR bacterial pathogens and treat recalcitrant infections.

Antimicrobial resistance profile and associated factors of hospital-acquired gram-negative bacterial pathogens among hospitalized patients in northeast Ethiopia

BackgroundAntimicrobial resistance is a major global public health issue. Infections caused by resistant species are associated with higher mortality rates, longer hospital stays, medication failure, and rising medical costs. The World Health Organisation has declared multidrug resistance-associated infections as an epidemic of public health concern.ObjectiveThis study aimed to evaluate the antimicrobial resistance profile and associated factors of hospital-acquired Gram-negative bacterial pathogens among hospitalized patients in Northeast Ethiopia.Materials and methodsA health facility-based cross-sectional study was conducted among hospitalized patients from March 2021 to February 2022. About 810 clinical specimens were collected, transported, and processed from admitted patients following the standard bacteriological procedures. The clinical samples were inoculated onto blood agar, MacConkey agar, and chocolate agar. Furthermore, the species identification was done using gram reactions, colony morphology, and color and biochemical tests. Antimicrobial susceptibility tests, extended-spectrum beta-lactamase, and carbapenemase production were performed as per the clinical laboratory standard institute guidelines. For analysis, the information was entered into Epi-data and exported to SPSS. A P value of < 0.05 with a 95% confidence interval was considered as a statistically significant association.ResultsOut of 810 clinical specimens, 285/810 (35.2%) developed bacterial infections. From the isolated bacteria, E. coli was the predominant bacteria accounting for 78/285 (27.4%) followed by K. pneumoniae, 69/285(24.42%), whereas P. vulgaris accounted for the least, 7/285 (2.5%). Overall, 132/285 (46.3%) and 99/285 (34.7%) of culture-positive patients were infected by extended-spectrum beta-lactamase and carbapenemase-producing bacteria. The overall multidrug resistance rate of the isolated bacteria was 89.4%. The highest antibiotic resistance rates were detected for doxycycline (92.9%), amoxicillin-clavulanic acid (83.9%), and ampicillin (93%). The least antibiotic resistance rate was observed for meropenem at 41.1% and amikacin at 1.7%, respectively.Conclusions and recommendationsIn the study area, significant health concerns include a range of hospital-acquired bacterial infections associated with elevated rates of multidrug resistance, Extended-spectrum beta-lactamase (ESBL), and carbapenemase-producing bacterial pathogens. Consequently, it is recommended to conduct drug-susceptibility testing of isolates and molecular detection at a national level to optimize antibiotic usage for treating prevalent bacterial infections in this area.

Fatty Acid Uptake in Klebsiella pneumoniae and the Landscape of Its Infectious Niches.

Klebsiella pneumoniae is consistently ranked among the most problematic multidrug-resistant bacterial pathogens in healthcare systems. Developing novel treatments requires a better understanding of its interaction with the host environment. Although bacteria can synthesize fatty acids, emerging findings suggest a potential preference for their acquisition from the host. Fatty acid profiling of mice revealed a dramatic increase in the level of hepatic lipids during K. pneumoniae infection. The K. pneumoniae fatty acid composition and uptake capabilities were found to be largely clonally conserved. Correlations between fatty acid uptake, outer membrane vesicle production, and cell permeability were observed, but this did not translate to alterations in cell morphology, capsule production, or antimicrobial susceptibility. Importantly, hyper-capsulation did not prevent the uptake of hydrophobic fatty acids. The uptake of a saturated fatty acid by hypervirulent K. pneumoniae isolate may provide insights into the clinical association of K. pneumoniae infections with hyperlipidemic and/or obese individuals.

The Road Ahead: Advancing Antifungal Vaccines and Addressing Fungal Infections in the Post-COVID World.

In impoverished nations, the COVID-19 pandemic has led to a widespread occurrence of deadly fungal diseases like mucormycosis. The limited availability of effective antifungal treatments and the emergence of drug-resistant fungal strains further exacerbate the situation. Factors such as systemic steroid use, intravenous drug misuse, and overutilization of broad-spectrum antimicrobials contribute to the prevalence of hospital-acquired infections caused by drug-resistant fungi. Fungal infections exploit compromised immune status and employ intricate mechanisms to evade immune surveillance. The immune response involves the innate and adaptive immune systems, leading to phagocytic and complement-mediated elimination of fungi. However, resistance to antifungals poses a challenge, highlighting the importance of antifungal prophylaxis and therapeutic vaccination. Understanding the host-fungal immunological interactions and developing vaccines are vital in combating fungal infections. Further research is needed to address the high mortality and morbidity associated with multidrug-resistant fungal pathogens and to develop innovative treatment drugs and vaccines. This review focuses on the global epidemiological burden of fungal infections, host-fungal immunological interactions, recent advancements in vaccine development and the road ahead.

Cannabinoids from C. sativa L.: Systematic Review on Potential Pharmacological Effects against Infectious Diseases Downstream and Multidrug-Resistant Pathogens

Cannabis sativa L. has garnered attention as a potential source for new antimicrobial agents, particularly due to the increased prevalence of microbial resistance to conventional antimicrobials and the emergence of multidrug-resistant pathogens. This review, conducted according to the PRISMA 2020 statement, systematically analyzed the antimicrobial properties of C. sativa extracts and cannabinoids against various bacteria, fungi, viruses, and parasites. Data were collected from the scientific literature (102 papers) and clinical trials (5 studies) from 2014 to June 2024. Findings revealed that cannabinoids, especially CBD, demonstrate significant antimicrobial activity against Gram-positive bacteria like MRSA, Gram-negative bacteria such as Pseudomonas aeruginosa, various Candida species, SARS-CoV-2, and HIV. Additionally, CBD showed efficacy against parasitic infections like Echinococcus granulosus and Leishmania species. These results suggest that cannabinoids may represent a new class of antimicrobial agents with unique and diverse mechanisms of action, potentially effective in broad-spectrum therapies. This study highlights the urgent need for further research and standardized clinical trials to validate these findings and to develop cannabinoid-based treatments. The antimicrobial properties of C. sativa align with WHO priorities and support global health initiatives, offering promising avenues for addressing antimicrobial resistance and improving public health outcomes.

Co-infections and secondary infections amid COVID-19 outbreaks in Vietnam

BackgroundThe mortality risk of co-infections/secondary infections (CoI/ScI) is under-reported in patients with non-critical COVID-19, leading to the under-management of CoI/ScI and publication bias in the medical literature. We aimed to investigate the association between CoI/ScI and mortality in patients hospitalised with mild-to-severe COVID-19.MethodsWe conducted a retrospective cohort study at a COVID-19 treatment hospital in Vietnam and collected all eligible medical records, with CoI/ScI status as the exposure (non-CoI/ScI and CoI/ScI, with the latter including nature of pathogen [bacterial, fungal, or bacterial + fungal] and multidrug-resistance pathogen [no MDRp or ≥ 1 MDRp]). The outcome was all-cause mortality, defined as in-hospital death by all causes or being discharged under critical illness. We used time-dependent analysis to report rates of mortality with 95% confidence intervals (95% CI, Poisson regression) and hazard ratios (HR) with 95% CI (Cox proportional hazards regression with Holm’s method for multiplicity control).ResultsWe followed 1466 patients (median age 61, 56.4% being female) for a median of 9 days. We recorded 387 (26.4%) deaths (95/144 [66.0%] in the CoI/ScI group and 292/1322 [22.1%] in the non-CoI/ScI group). Adjusted mortality rates (per 100 person-days) of the CoI/ScI (6.4, 95% CI 5.3 to 7.8), including bacterial (8.0, 95% CI 7.2 to 8.9), no MDRp (5.9, 95% CI 4.8 to 7.4), and ≥ 1 MDRp (9.0, 95% CI 8.2 to 10.0) groups were higher than that of the non-CoI/ScI group (2.0, 95% CI 1.8 to 2.2). These corresponded to higher risks of mortality in the overall CoI/ScI (HR 3.27, 95% CI 2.58 to 4.13, adjusted p < 0.001), bacterial CoI/ScI (HR 3.79, 95% CI 2.97 to 4.83, adjusted p < 0.001), no MDRp CoI/ScI (HR 3.13, 95% CI 2.42 to 4.05, adjusted p < 0.001), and ≥ 1 MDRp CoI/ScI group (HR 3.89, 95% CI 2.44 to 6.21, adjusted p < 0.001). We could not attain reliable estimates for fungal and bacterial + fungal CoI/ScI.ConclusionCompared with the non-CoI/ScI group, patients with CoI/ScI had a significantly higher risk of all-cause mortality, regardless of resistance status. More evidence is needed to confirm the mortality risks in patients with fungal or bacterial + fungal CoI/ScI.

Sourcing antimicrobial agents from Globimetula braunii: An in silico molecular docking and dynamic approach

The continued emergence of multi-drug resistance pathogens has been a major setback to lifting the burden of infectious diseases, especially bacterial illnesses. Natural- and/or nature-inspired compounds have so far become a therapeutic backbone on which many novel antibacterial agents are optimized. It is against this backdrop that we used an in silico molecular interaction-based approach to screen five previously identified compounds from Globimetula braunii, for lead inhibitors against bacterial illnesses. The compounds were chromatographed from the leaf ethyl acetate fraction and were characterized by spectroscopic means as 13,27-cycloursane (1), 13,27-cycloursan-3-one (2), methyl-3,5-dihydroxy-4-methoxybenzoate (3), 3-methyl-4-hydroxybenzoate (4), and 2-methoxyphenol (5). Upon their molecular docking at the active pocket of the Staphylococcus aureus gyrase B and the Escherichia coli DNA gyrase, 2 showed the highest binding affinities, with energy scores of -10 and -9.6 Kcal/mol. These were better than the standard antibiotics, Ampicillin (-7.5 and -8.0 Kcal/mol), and Ciprofloxacin (-6.9, -8.4 Kcal/mol). Further evaluation of the most promising compound 2 by molecular dynamics simulation showed the mean RMSD values of the 13,27-cycloursan-3-one - E. coli DNA gyrase protein complexes (complex 1) and 13,27-cycloursan-3-one - S. aureus gyrase B protein (complex 2) to be 0.7 and 0.9 Ǻ respectively, attaining stability at 102 and 108 ns. In contrast, complexes 1 and 2’s RMSF analysis revealed the fewest fluctuations and was generally stable over the course of the 120 ns. In conclusion, 13,27-cycloursan-3-one is unquestionably the most promising inhibitory candidate against the bacterial growth protein DNA gyrase, hence, it can be considered as a druggable substance against bacterial disease.

Phage-antibiotic synergy suppresses resistance emergence of Klebsiella pneumoniae by altering the evolutionary fitness.

Phage-antibiotic synergy (PAS) has been recently proposed as a superior strategy for the treatment of multidrug-resistant pathogens to effectively reduce bacterial load and slow down both phage and antibiotic resistance. However, the underlying mechanisms of resistance suppression by PAS have been poorly and rarely been studied. In this study, we tried to understand how PAS suppresses the emergence of resistance using a hypervirulent Klebsiella pneumoniae (KP) strain and a novel phage H5 in combination with ceftazidime (CAZ) as a model. Our study reveals a novel mechanism by which PAS drives altered evolutionary trajectory of bacterial populations, leading to suppressed emergence of resistance. The findings advance our understanding of how PAS suppresses the emergence of resistance, and are imperative for optimizing the efficacy of phage-antibiotic therapy to further improve clinical outcomes.

High-throughput screening identification of apigenin that reverses the colistin resistance of mcr-1-positive pathogens.

The plasmid-mediated gene mcr-1 that makes bacteria resistant to the antibiotic colistin is spreading quickly, which means that colistin is no longer working well to treat Gram-negative bacterial infections. Herein, we utilized a computer-aided high-throughput screening drugs method to identify the natural product apigenin, a potential mcr-protein inhibitor, which effectively enhanced the antimicrobial activity of colistin. Several assays, including a checkerboard minimum inhibitory concentration assay, a time-kill assay, the combined disk test, molecular simulation dynamics, and animal infection models assay, were conducted to verify whether apigenin enhanced the ability of colistin to fight Gram-negative bacterial infections. The results showed that apigenin improved the antimicrobial activity of colistin against multidrug-resistant Enterobacteriaceae infection. Moreover, apigenin not only did not increase the toxic effect of colistin but also had the ability to effectively inhibit the frequency of bacterial resistance mutations to colistin. Studies clearly elucidated that apigenin could interfere with the thermal stability of the protein by binding to the mcr-1 protein. Additionally, the combination of apigenin and colistin could exert multiple effects, including disrupting bacterial membranes, the generation of bacterial nitric oxide and reactive oxygen species, as well as inhibiting bacterial adenosine triphosphate production. Furthermore, the addition of apigenin was able to significantly inhibit colistin-stimulated high expression levels of the bacterial mcr-1 gene. Finally, apigenin exhibited a characteristic anti-inflammatory effect while enhancing the antimicrobial activity of colistin against mcr-1-positive Escherichia coli (E. coli) infected animals. In conclusion, as a potential lead compound, apigenin is promising in combination with colistin in the future treatment of mcr-1-positive E. coli infections.IMPORTANCEThis study found that apigenin was able to inhibit the activity of the mcr-1 protein using a high-throughput virtual screening method. Apigenin effectively enhanced the antimicrobial activity of colistin against multidrug-resistant Enterobacteriaceae, including mcr-1-positive strains, in vitro and in vivo. This study will provide new options and strategies for the future treatment of multidrug-resistant pathogen infections.

Genome sequences of 70 multidrug-resistant Gram-negative isolates in high-risk neonates in the Northeast of Mexico.

Infections by multidrug-resistant pathogens are steadily increasing worldwide. A considerable proportion of neonatal intensive care admissions have a bacterial infection with multidrug-resistant bacteria during their hospital stay. In this work, we report draft genome sequences of 70 selected isolates from high-risk neonates in the Northeast of Mexico.

Emergence of multidrug-resistant Providencia rettgeri clone in food-producing animals: A public health threat

The occurrence of carbapenemases encoding genes in Providencia rettgeri is a critical public health concern since this species has intrinsic resistance to several antimicrobials, including polymyxins. The identification of this multidrug-resistant (MDR) pathogen outside the hospital setting has become increasingly frequent, and raises an alert for the global health agencies, as they indicate a possible spread of such pathogens. Herein, we described three MDR P. rettgeri isolates carrying a diversity of antimicrobial resistance genes (ARGs) isolated from stool samples of swine and bovine in Brazil. Molecular analysis revealed that all isolates belonged to the same clone. The whole genome sequencing (WGS) of a representative isolate (PVR-188) was performed by MiSeq Illumina® platform, while the assembling and annotation was achieved using SPAdes and Prooka, respectively. The WGS analyses indicated the presence of ARGs that confer resistance to β-lactams (blaNDM-1, blaCTX-M-2), quinolones (qnrD1), aminoglycosides (aadA2, aadA1, aph(3′)-Via), phenicol (catB2), sulfonamides (sul1, sul2), and trimethoprim (dfrA12, dfrA1). The presence of three plasmid replicons (Col3M, IncQ1, and IncT) was detected, but no phage sequences were found. The phylogenetic analyses confirmed the genomic relationship of the PVR-188 with P. rettgeri isolates recovered from animals and humans in the USA and Malaysia. In conclusion, we report the occurrence of MDR P. rettgeri clone colonizing the gut microbiota of food-producing animals in Brazil, revealing the spread of this pathogen beyond hospital boundaries.