Drug-resistant Bacteria Research Articles

Antimicrobial resistance profile of bacteria from hospital wastewater at two specialized hospitals in Bahir Dar city, Ethiopia

BackgroundThe high levels of antimicrobial consumption in hospitals contribute to the occurrence of antimicrobial resistant bacteria. Antimicrobial resistant bacteria and sub-lethal concentrations of antimicrobial metabolites can end up in hospital wastewater which can spread to the environment and to the community. However, information on the resistance profile of bacteria isolated from environments is not well studied. Thus, the main aim of this study was to determine the antibiotic resistance profile of bacteria from hospital wastewater in Bahir Dar City, Northwest Ethiopia.MethodA total of 70 hospital wastewater samples were collected from two comprehensive specialized hospitals using a grab-sampling technique. Bacteria were identified using colony morphology, Gram staining, and biochemical tests. The drug susceptibility test was performed using the Kirby-Bauer disc diffusion method on Muller-Hinton agar.ResultThe most dominant bacterial isolates from hospital wastewater were Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Citrobacter spp., Acinetobacter spp., Enterobacter spp., Klebsiella pneumoniae (K. pneumoniae), and Pseudomonas aeruginosa (P. aeruginosa). All K. pneumoniae and 52.4% (11/21) E. coli were resistant to ceftazidime (third-generation cephalosporin), while Citrobacter spp., Acinetobacter spp., and Enterobacter spp., were susceptible to ceftazidime. Likewise, S. aureus revealed 64% (16/25) resistance to erythromycin. Overall, 22.2% of bacterial isolates were multidrug resistant bacteria to the commonly prescribed antimicrobials.ConclusionHospital waste waters contain high prevalence of multiple drug-resistant bacteria, particularly the third-generation cephalosporin resistant K. pneumoniae and E. coli would be a big concern. Infection prevention and control practices with proper treatment of hospital wastewater before discharging should be in practice to contain the spread of drug-resistant bacteria from hospital to external environment.

Screening of an Antibacterial and Coagulation Multifunctional Peptide and Its Application in Wound Healing.

As a new type of drug developed in the era of antibiotics, antimicrobial peptides (AMPs) have great potential in antibacterial, antiviral and antitumor aspects. Different from the principle of action of antibiotics, AMPs have a better effect on resisting drug-resistant bacteria. We synthesized a peptide library using solid-phase synthesis and successfully screened the antimicrobial peptide RKGAK. AMPs provide effective defense against both bacteria and fungi. Research has found that the lowest inhibitory concentrations of RKGAK against S. aureus, E. coli, and C. albicans are 75 μg/mL, 100 μg/mL, and 300 μg/mL. Not only that, this antibacterial peptide also has certain antiviral and coagulation effects. It is a multifunctional peptide that has great potential in many biomedical fields. It also has the advantages of being less likely to develop drug resistance, low hemolytic activity and low cytotoxicity. Loading the peptide into hydrogels has achieved good results in applications that promote wound healing.

Chitosan-Alginate Hydrogel Enriched with Hypericum perforatum Callus Extract for Improved Wound Healing and Scar Inhibition.

Hypericum perforatum callus contains pluripotent stem cells, and its extract (HPCE) is a natural compound that includes various biologically active components, such as phenolic acids, flavonoids, and naphthodiantrons like hypericin and hyperforin. These components give HPCE significant antibacterial and antioxidant properties, making it a valuable option for wound healing. Unlike traditional wound dressings that may leave a residue or necessitate invasive procedures like phototherapy, HPCE is a promising alternative. This study presents a hydrogel wound dressing made from a chitosan/alginate scaffold loaded with HPCE (CA/HPCE). This system displayed remarkable mechanical properties coupled with a high swelling capacity. Moreover, it demonstrated potent antibacterial, antioxidant, and anti-inflammatory activities, promoting a favorable environment for wound healing. In vitro studies confirmed that our wound dressings effectively inhibited Escherichia coli (E. coli) and drug-resistant bacteria like Klebsiella pneumoniae (K. pneumoniae), methicillin-resistant Staphylococcus aureus (MRSA), and methicillin-resistant coagulase-negative Staphylococcus (MR-CoNS). Additionally, CA/HPCE had the potential to significantly augment fibroblast migration. Moreover, in vivo investigations confirmed that this system accelerated re-epithelialization, neovascularization, and collagen deposition while reducing inflammation. Immunohistochemistry (IHC) analysis of α-smooth muscle actin (α-SMA) indicated the absence of hypertrophic scar formation postdressing. These findings suggest that CA/HPCE is a highly effective and innovative solution for advanced wound care.

Management of febrile neutropenia: consensus of the Brazilian Association of Hematology, Blood Transfusion and Cell Therapy - ABHH.

Febrile neutropenia is a major complication of the treatment of patients with hematologic diseases. Recent epidemiologic changes, with an increase in infection caused by drug-resistant bacteria, represent a major challenge for the proper management of febrile neutropenia. The impact of these changes in the epidemiology of infection may vary according to the region. In this document we present recommendations from the Infectious Diseases Committee of the Brazilian Association of Hematology, Blood Transfusion and Cell Therapy (ABHH) for the management of febrile neutropenia in hematologic patients. The consensus was developed by ten experts in the field, using the Delphi methodology. In the document we provide recommendations for the initial workup, prophylaxis, empiric antibiotic and antifungal therapy, modifications in the empiric regimen and criteria for discontinuing antimicrobial therapy.

Isolation, characterization, and potential application of Acinetobacter baumannii phages against extensively drug-resistant strains.

One of the significant issues in treating bacterial infections is the increasing prevalence of extensively drug-resistant (XDR) strains of Acinetobacter baumannii. In the face of limited or no viable treatment options for extensively drug-resistant (XDR) bacteria, there is a renewed interest in utilizing bacteriophages as a treatment option. Three Acinetobacter phages (vB_AbaS_Ftm, vB_AbaS_Eva, and vB_AbaS_Gln) were identified from hospital sewage and analyzed for their morphology, host ranges, and their genome sequences were determined and annotated. These phages and vB_AbaS_SA1 were combined to form a phage cocktail. The antibacterial effects of this cocktail and its combinations with selected antimicrobial agents were evaluated against the XDR A. baumannii strains. The phages exhibited siphovirus morphology. Out of a total of 30 XDR A. baumannii isolates, 33% were sensitive to vB_AbaS_Ftm, 30% to vB_AbaS_Gln, and 16.66% to vB_AbaS_Eva. When these phages were combined with antibiotics, they demonstrated a synergistic effect. The genome sizes of vB_AbaS_Ftm, vB_AbaS_Eva, and vB_AbaS_Gln were 48487, 50174, and 50043 base pairs (bp), respectively, and showed high similarity. Phage cocktail, when combined with antibiotics, showed synergistic effects on extensively drug-resistant (XDR) strains of A. baumannii. However, the need for further study to fully understand the mechanisms of action and potential limitations of using these phages is highlighted.

A Decade-Long Analysis of Trends in Antimicrobial Resistance in a Neurosurgical Hospital in Kathmandu, Nepal.

Multidrug-resistant (MDR) bacteria cause infections with higher risks of morbidity, mortality, and financial burden. Understanding the antimicrobial resistance patterns of these pathogens is crucial for effective treatment and managing resistance. Therefore, this retrospective study examined the prevalence, causes, and trends in antimicrobial resistance in bacterial infections at a neurosurgical hospital in Nepal. We analyzed the demographics, bacteriological profiles, and antimicrobial susceptibility results in patients who visited Dirghayu Guru Hospital and Research Center, Kathmandu, Nepal, between January 2014 and January 2024, using SPSS, version 17.00. Among 4758 patients, 465 (9.77%) had infections caused by 571 bacteria. Of them, 435 (93.55%) patients had urinary tract infections, 89 (19.14%) had bloodstream infections, and 31 (6.67%) had respiratory tract infections. Klebsiella pneumoniae (n = 172, 30.12%) was the predominant bacteria. Proportions of drug-resistant Enterobacterales and gram-positive cocci among drug-resistant bacteria against tetracyclines were 83.33% and 45.83%, cephalosporins were 78.02% and 40.45%, quinolones were 72.25% and 50.00%, aminoglycosides were 65.14% and 43.53%, carbapenems were 62.96% and 30.00%, penicillins were 54.55% and 57.89%, and penicillin with beta-lactamase inhibitors (PwBLIs) were 40.54% and 42.31%, respectively. Proportions of drug-resistant nonfermenters among drug-resistant bacteria showed 100.00% resistance to these antimicrobials. MDR isolates (n = 118, 20.67%) were 100.00% susceptible to piperacillin-tazobactam and 83.33% to polymyxin B. Over the years, resistance increased for cephalosporins (48.15%-60.53%) but decreased for carbapenems (50.00%-33.33%), penicillins (64.29%-42.31%), PwBLIs (50.00%-12.50%), aminoglycosides (60.00%-49.12%), tetracyclines (100.00%-16.67%), and polymyxins (76.22%-16.67%). One-tenth of hospital-visiting patients had bacterial infections, with three-fourths involving Enterobacterales and one-fifth involving MDR bacteria. In recent years, resistance to cephalosporins has increased, whereas resistance to other beta-lactams, aminoglycosides, and polymyxins has decreased.

Microneedles Constructed by Swellable Hydrogels Loaded with Celastrol for Efficient Treatment of Skin Infections Induced by Drug-Resistant Bacterial Strains.

The urgent need for new antimicrobial drugs arises from the limited efficacy of traditional antibiotics against emerging drug-resistant strains. Celastrol (CSL) demonstrates an exceptional antibacterial property that remains unaffected by bacterial resistance, but its poor water solubility limits its wide applications. This study uses the hydrophobic inner cavity of mono-(6-diethylenetriamine-6-deoxy)-β-cyclodextrin (mβ-CD) (a derivative of cyclodextrin) to encapsulate CSL, constructing an inclusion complex (CSL@mβ-CD) to enhance the water solubility of CSL. The obtained inclusion complex is further incorporated into a swellable hydrogel microneedle (MN) to obtain CSL@mβ-CD/MN. The fabricated CSL@mβ-CD/MN can enable the sustained release of CSL, achieving effective bacterial eradication at infected sites. In vivo experiments demonstrate that CSL@mβ-CD/MN has a remarkable efficacy in the treatment of methicillin-resistant Staphylococcus aureus-induced subcutaneous abscesses and wound infections. Specifically, CSL@mβ-CD/MN can effectively penetrate the stratum corneum of the skin to realize rapid elimination of the bacteria in wounds. Moreover, CSL@mβ-CD/MN can efficiently scavenge reactive oxygen species, promote M2 polarization of macrophages, and relieve local inflammation at the wound sites. These results reveal that CSL@mβ-CD/MN holds great promise in the clinical treatment of acute skin infections induced by drug-resistant bacteria.

Design, Synthesis, and Activity Evaluation of C-23-Modified 5-O-Mycaminosyltylonolide Derivatives.

The widespread use of tylosin family drugs in clinical practice has led to bacterial resistance and reduced therapeutic efficacy. We designed and synthesized a series of new semisynthetic derivatives of tylosin with 5-O-mycaminosyltylonolide as the mother nucleus, mainly by introducing a variety of amino groups at its C-23 position. Some of the compounds showed high antibacterial activity against Gram-negative and Gram-positive bacteria. These findings indicate that the best compound, c9, possessed significant antibacterial activity (MIC = 0.5 ug/mL), excellent bactericidal efficacy, and a low induction rate of drug resistance against Staphylococcus aureus and Escherichia coli; it also showed good antibacterial activity against drug-resistant bacteria. In addition, compound c9 has a low toxicity in vitro and in vivo. In conclusion, compound c9 could be a potential antimicrobial lead compound that could also contribute to the development of macrolide antibiotics.

Synthesis and potent antibacterial activity of nano-CuFe2O4/MoS2@Ag composite under visible light

With antibiotic resistance on the rise due to misuse, the urgent need for new antibacterial materials has become paramount in global health. Herein, a CuFe2O4/MoS2 (CFM) composite with a large specific surface area was synthesized through a simple hydrothermal method and physical adsorption, and the subsequent loading of silver nanoparticles (Ag NPs) onto its surface yielded the nanocomposite CuFe2O4/MoS2@Ag (CFMA) with a rough defect-rich surface. The nanocomposite demonstrates remarkable antibacterial activity against Escherichia coli, Staphylococcus aureus, and drug-resistant Salmonella (T-Salmonella) by releasing metal ions that alter the electrical potential of bacterial cell membranes, compromise the integrity of cell membranes, and produce reactive oxygen species that lead to oxidative stress. It thus achieves an antibacterial rate of 96 % against the three tested bacterial strains within just 20 min at a concentration of 200 μg/mL. The composite exhibits a broad-spectrum antibacterial effect against Gram-negative and Gram-positive bacteria, as well as drug-resistant bacteria. Moreover, CFM acts as a carrier that effectively prevents the aggregation of Ag NPs, and the magnetism of CuFe2O4 facilitates the recovery of the antibacterial agent. This work provides new ideas and methods for the development of highly efficient, cost-effective, and biocompatible antibacterial materials.

The Effect of Chalcogen-Chalcogen Bond Formation in the New Delhi Metallo-β-Lactamase 1 Enzyme to Counteract Antibiotic Resistance.

New Delhi metallo-β-lactamase 1 (NDM-1) is an enzyme involved in the drug resistance of many bacteria against most of the widely adopted antibiotics, such as penicillins, cephalosporins, and carbapenems. Consequently, inhibiting NDM-1 swiftly has gained significant interest as a strategy to counteract this bacterial defense mechanism, thereby restoring the effectiveness of antibiotics. Among the inhibitors tested against the enzyme, ebselen (EbSe) showed particularly promising results. This molecule, renowned for its numerous benefits to the human body, targets the enzyme's active site at Cys208 with its selenium atom, facilitating the expulsion of the catalytic zinc ion from the active pocket. Since the inhibitory mechanism of EbSe remains poorly understood, gaining detailed information about it is highly desirable. In the present work, density functional theory calculations and μs-long molecular dynamics simulations are carried out to investigate the reaction mechanism of EbSe with NDM-1, unveiling the structural implications of the inhibition. A large model of the NDM-1 active site is built to investigate the different mechanistic proposals for the SeEbSe-SCys208 bond formation. Deeper insights into Lys211 are also provided to consolidate its role during the inhibition process. Furthermore, the chemical reaction with the ebsulfur (EbS) molecule is also investigated to compare its behavior with that of the periodic relative selenium. Molecular dynamics simulations, besides evidencing the role of the L3 and L10 loops in the occurrence of the inhibition, corroborate the Zn ion release from the active site as a result of the complete disruption of its coordination sphere caused by the creation of the SeEbSe-SCys208 covalent bond.

The upconversion luminescence biomonitoring and biological properties of rare earth oxide-inorganic composite microspheres enhanced by lithium

Multiple myeloma is the second most common hematologic malignant tumor, which can result in complications such as osteolytic fractures and bacterial infections. The side effects of chemotherapy limit the dosage of drugs, which can easily lead to multidrug resistance. Moreover, the dose and distribution of drugs within the body significantly influence the therapeutic efficacy of drugs. Therefore, it is highly necessary to improve multidrug resistance and bacterial infection in the treatment of multiple myeloma, repair bone defects caused by bone pain, and monitor the real-time dynamics of drugs. This work proposes a novel rare earth oxide-inorganic composite (7Li-MBGs:2Er/2Yb-0.75MTO) as a drug delivery platform for the treatment of multiple myeloma. 7Li-MBG, which have bone repair functions, serve as inorganic matrix materials, while Er2O3 and Yb2O3 act as activators and sensitizers, respectively. MTO is used as a therapeutic drug for treating myeloma. The drug release process of MTO was successfully monitored by upconversion luminescence. Cell experiments confirmed that 7Li-MBGs:2Er/2Yb-0.75MTO has a certain long-term therapeutic effect on multiple myeloma, and its mechanism of action is consistent with its drug release kinetics. Moreover, the synergistic effect of rare earth oxides, alkali metal ions and MTO endows 7Li-MBGs:2Er/2Yb-0.75MTO with high antibacterial and osteoinductive abilities, and thus playing a role in enhancing the drug resistance of infectious bacteria, preventing bacterial infection, repairing bone defects and monitoring the real-time dynamics of drug release during multiple myeloma therapy. Therefore, the 7Li-MBGs:2Er/2Yb-0.75MTO multifunctional drug delivery platform synthesized in this work provides a new idea for the treatment of multiple myeloma and biomonitoring.

Identification and characterization of a novel bacteriocin PCM7-4 and its antimicrobial activity against Listeria monocytogenes

Listeria monocytogenes, a pathogenic bacterium causing zoonotic diseases, necessitates the urgent search for novel anti-Listeria monocytogenes drugs due to the continuous emergence of drug-resistant bacteria. In this study, we isolated and identified a bacteriocin-producing strain CM7–4 from seawater as Bacillus velezensis through 16S rRNA sequence analysis. Moreover, we successfully purified a novel bacteriocin named PCM7–4 from Bacillus velezensis CM7–4. The molecular weight of PCM7–4 was determined to be 40,228.99 Da. Notably, PCM7–4 exhibited broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria with a minimum inhibitory concentration (MIC) of 5.625 μg/mL against Listeria monocytogenes specifically. It demonstrated heat resistance and high stability within the pH range of 2–12 while being sensitive to proteinase K degradation without any observed hemolytic activity. Furthermore, SEM analysis revealed that PCM7–4 effectively inhibited biofilm formation and disrupted cell membranes in Listeria monocytogenes cells. Transcriptome analysis revealed that PCM7–4 exerts an impact on genes associated with crucial metabolic pathways, encompassing the biosynthesis of secondary metabolites, phosphotransferase systems (PTS), and starch/sucrose metabolism. These findings highlight the significant potential of bacteriocin PCM7–4 for the development of effective antimicrobial interventions targeting food-borne pathogenic bacteria.

New 3-acyl derivatives of glaucocalyxin A: designed, synthesis and in vitro antibacterial activities

To discover novel antimicrobial drug, 22 novel acylated derivatives were synthesized by A-ring modification of glaucocalyxin A. The structures of these derivatives were confirmed by NMR and MS data. In vitro antimicrobial activity of these compounds was evaluated against E. faecium, E. faecalis, MRSA, E. coli, A. baumannii and K. pneumoniae. The results showed compound 3d against E. faecium, E. faecalis and MRSA with a minimum inhibitory concentration of 4 μg/ml. And further molecular docking revealed that compound 3d has a higher binding affinity. In conclusion, compound 3d has the potential to develop into a new drug against drug-resistant bacteria.

Ultralow Dose Iron-Copper Bimetallic Single-Atom Nanozymes for Efficient Photothermal-Chemodynamic Antibacterial and Wound Healing.

The combination of photothermal and chemodynamic therapy (PTT-CDT) using single-atom nanozymes (SAzymes) shows great promise in combating pathogenic and drug-resistant bacteria. However, the photothermal conversion efficiency and catalytic activity of SAzymes with solely metal sites remain inadequate, often requiring high doses for effectiveness. Herein, a bimetallic single-atomic nanozymes with Fe and Cu active sites (FeCu BSNs) designed is reported for efficient treatment of bacterial infections through hyperthermia-amplified nanozyme catalysis strategy. The FeCu BSNs demonstrate remarkable peroxidase (POD) activity with a specific activity (SA) of 752.25 U mg-1, which is 2.3 folds larger than that of Fe SAzymes (323.45 U mg-1). Additionally, their photothermal effect achieve a photothermal conversion efficiency up to 56.26%, which is two times higher that of Fe SAzymes (29.69%) and Cu SAzymes (25.55%). These enhancements can be attributed to the hybridization of Fe and Cu sites. The FeCu BSNs-mediated PTT-CDT combination therapy demonstrates potent antibacterial effects in both in vitro and in vivo models, attributed to high levels of reactive oxygen species (ROS)generation and hyperthermia. This study effectively validates the application of ultralow-dose bimetallic single-atom nanozymes in PTT-CDT for wound healing, offering a promising approach for enhanced wound recovery.

Two birds with one stone: Mussel-inspired anchoring strategy enabling full-spectrum utilization and superior carriers transfer capacity for efficient photocatalytic degradation and antibacterial

Antibiotic pollution that often leads to the increases in the prevalence of resistance represents unneglectable risks to human health. Photocatalysis shows great potential in addressing the antibiotic pollution issue. However, developing photocatalysts integrating full-spectrum photocatalysis and self-adaptive antibacterial performances still remains challenges due to the limited utilization rate of light and carrier transfer capacity. Herein, a mussel-inspired anchoring strategy was employed to fabricate polydopamine coated Hydrothermal carbon carbide ZIF-8ZnO (PDA@HTCC/ZIF-8ZnO) heterojunction photocatalyst. The PDA coating was used as a transition layer to promote the heterogeneous nucleation of ZIF-8 on HTCC. Benefiting from the interfacial connections formed by metal coordination interactions between catechol groups of PDA coating and metal sites of ZIF-8, the carrier transfer capacity of PDA@HTCC/ZIF-8ZnO was improved and the range of light that can be utilized for the PDA@HTCC/ZIF-8ZnO was broadened. Therefore, the PDA@HTCC/ZIF-8ZnO heterojunction presented outstanding full-spectrum photocatalytic degradation and antibacterial performances. The full-spectrum degradation efficiency of tetracycline by PDA@HTCC/ZIF-8ZnO reached 98.7 % in 50 min. Moreover, the antimicrobial efficacy of PDA@HTCC/ZIF-8ZnO against E. coli exceeded 90 % under both light and dark conditions. The promotion effect of PDA transition layer on electrons transfer has been confirmed by DFT calculations. Under light irradiation, PDA@HTCC/ZIF-8ZnO gradually degrades tetracycline through demethylation, deamination, decarboxylation reactions, and ring-opening reactions, ultimately generating CO2 and H2O. This innovative strategy benefits the future heterojunction photocatalysts design for efficient solution of antibiotics pollution and the derivative drug-resistant bacteria issues.

Antimicrobial peptides-a promising novel antimicrobial agent

Abstract. Antibiotic resistance has become one of the most critical public health problems in the 21st century, and infections caused by drug-resistant bacteria severely threaten human health. Otherwise, the development rate of conventional antibiotics has been unable to keep up with the speed at which bacteria develop resistance. Therefore, it is urgent to develop antimicrobial agents with novel mechanisms of action. Antimicrobial peptides (AMPs) are naturally occurring polypeptides with antibacterial activity, which have different mechanisms of action from existing antibiotics and thus have incomparable advantages over traditional antibiotics in treating infections caused by drug-resistant bacteria. Up to now, AMPs have been used in several clinical studies to destroy drug-resistant bacteria. The review introduces the basic properties of AMPs and their therapeutic mechanisms, summarizes some advances in preclinical studies and clinical applications, and analyzes the factors limiting their application in clinical treatment. In addition, some new strategies to overcome the shortcomings of AMPs in clinical applications are also introduced. Efficient and diverse synthesis technologies and optimization strategies keep coming to overcome the difficulties of clinical applications for AMPs, which may become an important weapon against drug-resistant bacterial infections in the future.

Mycosynthesis of silver nanoparticles from endophytic Aspergillus parasiticus and their antibacterial activity against methicillin-resistant Staphylococcus aureus in vitro and in vivo.

Methicillin-resistant Staphylococcus aureus (MRSA) is a drug-resistant and biofilm-forming pathogenic bacteria with severe morbidity and mortality. MRSA showed resistance against currently available antibiotics. Thus, there is an urgent need to develop novel effective treatments with minimal side effects to eliminate MRSA. In this study, we aimed to mycosynthesize silver nanoparticles (AgNPs) using the endophytic fungus Aspergillus parasiticus isolated from leaves of Reseda Arabica and to examine their antibacterial activity against MRSA. Screening of fungal secondary metabolites using gas chromatography-mass spectroscopy (GC-MS) analysis revealed the presence of high content of bioactive compounds with antibacterial activities. AP-AgNPs were mycosynthesized for the first time using ethyl acetate extract of A. parasiticus and characterized by imaging (transmission electron microscopy (TEM), UV-Vis spectroscopy, zeta potential, X-ray diffraction (XRD), energy-dispersive X-ray analysis (EDX), and Fourier transform infrared spectroscopy (FTIR)). The agar well diffusion method revealed the antibacterial activity of AP-AgNPs against MRSA with 25 μg/mL of minimum inhibitory concentration (MIC). AP-AgNPs were shown to exert antibacterial action via a bactericidal mechanism based on flow cytometry, scanning electron microscopy, and transmission electron microscopy assessment. Our data demonstrated the effective interaction of AP-AgNPs with the bacterial cell membrane, which resulted in cell membrane damage and disruption of cell surface structure. Furthermore, AP-AgNPs successfully prevented the development of MRSA biofilms by disturbing cell adhesion and destructing mature biofilm reaching over 80% clearance rate. Interestingly, topical application of AP-AgNPs to superficial skin infection induced by MRSA in mice effectively promoted wound healing and suppressed bacterial burden. Our results provide a novel green nanoparticle drug design with effective therapeutic potential against MRSA-induced skin infection.

Incidence of colistin heteroresistance among carbapenem-resistant Acinetobacter baumannii clinical isolates in a tertiary care hospital in Pakistan.

The emergence of colistin-resistant and heteroresistant strains of carbapenem-resistant Acinetobacter baumannii (CRAB) complicates treatment and exacerbates the global health crisis of drug-resistant bacteria. This study aims to investigate the incidence and clinical implications of colistin heteroresistance in carbapenem-resistant Acinetobacter baumannii isolates from a tertiary hospital in Pakistan. A total of 130 CRAB isolates were collected from December 2022 to December 2023. Colistin susceptibility was assessed using broth microdilution, and heteroresistance was detected through population analysis profiling. Heteroresistance (HR) was identified in 31.5% (41/130) of the isolates, while 7.7% were colistin-resistant, despite initial susceptibility indicated by broth microdilution. Clinical data revealed that HR was associated with significant 14-day clinical failure but not with 30-day all-cause mortality. Heteroresistant strains showed extensive multidrug resistance, posing a serious threat to effective treatment. The study highlights the critical need for accurate detection of colistin HR to prevent treatment failure and improve patient outcomes. The prevalence of colistin HR underscores the necessity for revised diagnostic and treatment strategies in Pakistan, emphasizing the importance of recognizing and addressing this emerging threat in healthcare settings.

Discovery of new AMR drugs targeting modulators of antimicrobial activity using in vivo silkworm screening systems.

Global concerns about drug-resistant bacteria have underscored the need for new antimicrobial drugs. Emerging strategies in drug discovery include considering the third factors that influence drug activity. These factors include host-derived elements, adjuvants, and drug combinations, which are crucial in regulating antimicrobial efficacy. Traditional in vivo assessments have relied on animal models to study drug absorption, distribution, metabolism, excretion, and toxicity (ADMET). Alternative models, such as silkworms, are being explored to overcome the ethical and financial barriers associated with mammalian models. The silkworm has been proven effective in evaluating ADMET and in highlighting the therapeutic potential enhanced by third factors. Host factors (either mammalian or non-mammalian) enhance the antimicrobial activity of antimicrobial agents such as lysocin E. Additionally, using D-cycloserine to potentiate vancomycin has successfully combated vancomycin-resistant infections in silkworms. Leveraging silkworms in drug discovery could establish a novel screening method incorporating interactions with third factors, whether host related or non-host-related, thus promising new pathways for identifying antimicrobial drugs with unique mechanisms of action.

Stereorandomized Oncocins with Preserved Ribosome Binding and Antibacterial Activity.

We recently showed that solid-phase peptide synthesis using racemic amino acids yields stereorandomized peptides comprising all possible diastereomers as homogeneous, single-mass products that can be purified by HPLC and that stereorandomization modulates activity, toxicity, and stability of membrane-disruptive cyclic and linear antimicrobial peptides (AMPs) and dendrimers. Here, we tested if stereorandomization might be compatible with target binding peptides with the example of the proline-rich AMP oncocin, which inhibits the bacterial ribosome. Stereorandomization of up to nine C-terminal residues preserved ribosome binding and antibacterial effects including activities against drug-resistant bacteria and protected against serum degradation. Surprisingly, fully stereorandomized oncocin was as active as L-oncocin in dilute growth media stimulating peptide uptake, although it did not bind the ribosome, indicative of an alternative mechanism of action. These experiments show that stereorandomization can be compatible with target binding peptides and can help understand their mechanism of action.