The Engineered Antibiotic Peptide PLG0206 Eliminates Biofilms and Is a Potential Treatment for Periprosthetic Joint Infections

Antimicrobial peptides (AMPs) have recently gained attention for their potential to treat diseases related to bacterial and viral infections, as many traditional antimicrobial drugs have reduced efficacy in treating these infections due to the increased prevalence of drug-resistant pathogens. PLG0206, an engineered cationic antibiotic peptide that is 24 residues long, has been designed to address some limitations of other natural AMPs, such as toxicity and limited activity due to pH and ion concentrations. Nonclinical studies have shown that PLG0206 is highly selective for targeting bacterial cells and is not toxic to human blood cells. Antibiofilm experiments demonstrated that PLG0206 is effective at reducing both biotic and abiotic biofilm burdens following direct biofilm contact. PLG0206 has rapid and broad-spectrum activity against both Gram-positive and Gram-negative bacteria that are implicated as etiologic agents in periprosthetic joint infections, including multidrug-resistant ESKAPE pathogens and colistin-resistant isolates. A recent first-in-human study demonstrated that PLG0206 is well tolerated and safe as an intravenous infusion in healthy volunteers. Studies are planned to determine the efficacy of PLG0206 in patients for the treatment of periprosthetic joint infections. This review summarizes the chemistry, pharmacology, and microbiology of PLG0206 and explores its current preclinical, clinical, and regulatory status.

Efficacy and Safety of Levonadifloxacin in the Management of Community-Acquired Bacterial Pneumonia (CABP): Findings of a Retrospective, Real-World, Multi-centre Study

Background: Community-acquired bacterial pneumonia (CABP) remains a global public health threat and is a leading cause of hospitalization and infection-linked mortality. Levonadifloxacin is a novel benzoquinolizine antibiotic with a broad-spectrum activity including methicillin-resistant Staphylococcus aureus (MRSA) and CABP-pathogens. Methods: This multi-centre, retrospective, post-marketing, real-world study assessed the efficacy and safety of levonadifloxacin oral and/or intravenous therapy in the treatment of CABP. Data from 338 patients above 17 years-of-age who received levonadifloxacin (oral or intravenous or both) was collected from 89 healthcare facilities across India. Information on clinical condition, comorbidities, complications, and details of concurrent therapy (including antimicrobial agents) was also collected. Study outcomes were clinical and microbial success at the end of therapy while safety was assessed based on clinical and laboratory adverse events. Results: Of the 338 patients, 244 (72.2%) were male, 93 (27.5%) were female and 1 (0.43%) was a transgender. About 294 (87.0%) patients were hospital-treated and 44 (13%) received outpatient treatment. About 248 (73.4%) patients received intravenous levonadifloxacin treatment, 79 (23.4%) received oral and 11 (3.3%) received intravenous followed by oral levonadifloxacin therapy. The common comorbid conditions were diabetes (14.2%) and hypertension (8.6%). Mean duration of levonadifloxacin therapy was 6.4 days. Clinical and microbial success in levonadifloxacin-treated patients was 95.0% (321/388) and 96.8% (150/155), respectively. Conclusions: Levonadifloxacin showed promising clinical outcomes and safety when used as an intravenous and/or oral for the treatment of CABP, both in outpatients as well as hospitalized patients.

Review on Antifungal Agents

There are so many type of daisies are founded because of ‘Fungal’ such daisies given in follow. also the treatment on this particular daisies with the help of ‘Anti-fungal’ drug or anti- fungal agent and anti-fungal medication as follows The four main classes of antifungal drugs are the polyenes, Azoles, allylamines and echinocandins. Clinically useful “older” agents include topical azole Formulations (for superficial yeast and dermatophyte Infections), first-generation triazoles (fluconazole and Itraconazole, for a range of superficial and invasive fungal Infections), amphotericin B formulations (for a broad range of Invasive fungal infections) and terbinafine (for dermatophyte Infections). Clinically important “newer” agents include members of the Echinocandin class (eg, caspofungin) and second-generation Triazoles (eg, voriconazole and posaconazole). Voriconazole and posaconazole have broad-spectrum activity Against yeasts and moulds, including Aspergillus species. Posaconazole is the only azole drug with activity against Zygomycete fungi. Caspofungin and the other echinocandins are effective in Treating Candida and Aspergillus infections. The azoles are relatively safe, but clinicians should be aware of drug–drug interactions and adverse effects, including Visual disturbances (with voriconazole), elevations in liver Transaminase levels, and skin rashes. Caspofungin has Minimal adverse effects. Combination antifungal therapy may be appropriate in Selected patients with invasive fungal infections, but is Empiric and driven by individual physician practice. Clinical needs for novel antifungal agents have altered

Structural, optical, and potential broad-spectrum antibacterial properties of CuO-Ag nanoparticles biosynthesized using the extract of Diospyros discolor Willd

The development of new material properties for antimicrobial agents to address the problem of antibiotic resistance is currently being explored. Silver and copper exhibit oligodynamic properties, which inhibit the growth of microorganisms. These properties are stronger at the nanoscale than the macroscale, especially for bimetallic nanoparticles (NPs). In this study, we synthesized bimetallic CuO and Ag NPs using Diospyros discolor Willd. (Velvet apple) leaf extract with three different ratios of Cu and Ag precursors: 1:0.01, 1:0.1, and 1:1 (v/v). In addition, the optical properties of these NPs were characterised using UV-Vis spectrophotometer, which showed the typical absorbance peak in the range of 300–400 nm. The size and shape of the CuO and Ag nanoparticles were analysed using a scanning electron microscope (SEM) and transmission electron microscope (TEM) images. The SEM and TEM images showed leaf-shaped CuO nanoplates and spherical AgNPs. Furthermore, the crystalline properties were analysed using x-ray diffraction (XRD). This study produced CuO-Ag nanoclusters with a particular morphology, size, and composition. The antibacterial assay showed potential broad-spectrum activity for Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) as well as Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa).

Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity

Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development.

NUDT18 catalyzes hydrolysis of active metabolites of the antivirals Remdesivir and Ribavirin

Remdesivir (GS-5734) has gained considerable interest due to its activity against replication of SARS-CoV2. Remdesivir is a broad-spectrum antiviral prodrug that is hydrolyzed intracellularly and phosphorylated by cellular kinases to its active triphosphate form (Remdesivir-TP). Here we tested Remdesivir-TP as a substrate for a panel of human hydrolases and found that NUDIX hydrolase 18 (NUDT18) catalyzes the hydrolysis of Remdesivir-TP. NUDT18 is expressed in respiratory epithelial cells suggesting that NUDT18 may limit the antiviral efficacy of Remdesivir by decreasing the intracellular concentration of its active metabolite at its intended site of action. The kcat of NUDT18 for Remdesivir-TP was determined to 2.6 s-1 and the Km value was 156 μM, suggesting that NUDT18 catalyzed hydrolysis occurs in cells. In addition, we found that the triphosphate of the antiviral Ribavirin, with broad-spectrum activity against several RNA and DNA viruses, was hydrolyzed by NUDT18, albeit with a lower efficiency compared to Remdesivir-TP. NUDT18 activity was also tested with the triphosphates of the antivirals Sofosbuvir and Aciclovir for which low activity, in comparison to activities with Remdesivir-TP and Ribavirin-TP, was detected. These results suggest that NUDT18 can act as a cellular sanitizer and may influence the antiviral efficacy of Remdesivir and Ribavirin.

The antibacterial activity of isatin hybrids

: Bacterial infections which cause a wide range of host immune disorders leading to local and systemic tissue damage, are still one of the main causes of patient morbidity and mortality worldwide. Treatment of bacterial infections is challenging, which is mainly attributed to the rapidly evolving resistance mechanisms, creating an urgent demand to develop novel antibacterial agents. Hybridization is one of the most promising strategies in the development of novel antibacterial drugs with the potential to address drug resistance since different pharmacophores in the hybrid molecules could modulate multiple targets and exert synergistic effects. Isatin, distributed widely in nature, can exert antibacterial properties through acting on diverse enzymes, proteins, and receptors. Accordingly, hybridization of isatin pharmacophores with other antibacterial pharmacophores in one molecule may provide novel antibacterial candidates with broad-spectrum activity against various pathogens, including drug-resistant forms. This review aims to outline the recent advances of natural and synthetic isatin hybrids with antibacterial potential and summarize the structure-activity relationship (SAR) to provide an insight for the rational design of more active candidates, covering articles published between January 2012 and June 2021.

A drug repurposing screen identifies altiratinib as a selective inhibitor of a key regulatory splicing kinase and a potential therapeutic for toxoplasmosis and malaria

The apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that infect humans and animals and cause severe parasitic diseases. Available therapeutics against these devastating diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. Here, we use a drug repurposing strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index. We have identified TgPRP4K of T. gondii as the primary target of altiratinib by genetic target deconvolution, highlighting key residues within the kinase catalytic site that, when mutated, confer resistance to the drug. We have further elucidated the molecular basis of the inhibitory mechanism and species selectivity of altiratinib for TgPRP4K as well as for its P. falciparum counterpart PfCLK3. Our data also point to structural features critical for binding of the other PfCLK3 inhibitor, TCMDC-135051. Consistent with the role of this kinase family in splicing in a broad spectrum of eukaryotes, we have shown that altiratinib causes global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum. Thus, our data establish parasitic PRP4K/CLK3 as a promising pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib.

Development of Novel Peptides for the Antimicrobial Combination Therapy against Carbapenem-Resistant Acinetobacter baumannii Infection

Carbapenem-resistant Acinetobacter baumannii (CRAB) infection has a high mortality rate, making the development of novel effective antibiotic therapeutic strategies highly critical. Antimicrobial peptides can outperform conventional antibiotics regarding drug resistance and broad-spectrum activity. PapMA, an 18-residue hybrid peptide, containing N-terminal residues of papiliocin and magainin 2, has previously demonstrated potent antibacterial activity. In this study, PapMA analogs were designed by substituting Ala15 or Phe18 with Ala, Phe, and Trp. PapMA-3 with Trp18 showed the highest bacterial selectivity against CRAB, alongside low cytotoxicity. Biophysical studies revealed that PapMA-3 permeabilizes CRAB membrane via strong binding to LPS. To reduce toxicity via reduced antibiotic doses, while preventing the emergence of multi-drug resistant bacteria, the efficacy of PapMA-3 in combination with six selected antibiotics was evaluated against clinical CRAB isolates (C1–C5). At 25% of the minimum inhibition concentration, PapMA-3 partially depolarized the CRAB membrane and caused sufficient morphological changes, facilitating the entry of antibiotics into the bacterial cell. Combining PapMA-3 with rifampin significantly and synergistically inhibited CRAB C4 (FICI = 0.13). Meanwhile, combining PapMA-3 with vancomycin or erythromycin, both potent against Gram-positive bacteria, demonstrated remarkable synergistic antibiofilm activity against Gram-negative CRAB. This study could aid in the development of combination therapeutic approaches against CRAB.