Repurposing the Antibacterial Activity of the Drug Teniposide Against Gram‐Positive Bacteria

Drug repurposing is sparking considerable interest due to reduced costs and development times. The current study details the screening of teniposide, an antitumor drug, for its antibacterial activity against both Gram-positive and Gram-negative strains, with a focus on Staphylococcus epidermidis (S. epidermidis), the primary causative agent of nosocomial and transplant-related infections. The cytotoxicity was evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and hemolysis assays on immortalized human keratinocyte (HaCaT) cells and human erythrocytes. After 20 h of treatment, the recorded concentrations causing 50% cytotoxicity (CC50) and hemolysis (HC50) were 33.63 and 121.55 μg/mL, respectively. The antibacterial screening employed disk diffusion, the broth microdilution method, LIVE/DEAD staining, and a time-killing test. The drug induced a growth inhibitory area in the 22–25 mm range for all Gram-positive strains. The minimum concentration that inhibited 90% of bacteria (MIC90) was 6.25 μg/mL against Staphylococcus aureus and S. epidermidis and 12.5 μg/mL versus Enterococcus faecalis, exhibiting bactericidal action. Treatment resulted in S. epidermidis cell morphology deformities and damage to the cell membrane, observed by scanning electron microscopy (SEM). Mechanism analysis revealed alterations in the selective permeability of the cell membrane, observed under the fluorescence microscope by the absorption of propidium iodide (PI). The synergistic effect of teniposide in combination with fosfomycin and gentamicin was documented by disk diffusion and checkboard assay, recording a fractional inhibitory concentration index (FICI) of 0.28 and 0.37, respectively. The drug’s action on S. epidermidis biofilm biomass was investigated using crystal violet (CV) and MTT. Teniposide affected biofilm viability in a dose-dependent manner, inducing, at a concentration of 3.12 μg/mL, a matrix inhibition of about 42% and 61%, with a sessile metabolic activity of 54% and 24% recorded after 2 and 24 h, respectively. Overall, this study suggests the potential repurposing of the anticancer drug teniposide as a therapeutic agent to counteract S. epidermidis infections

Group V Secreted Phospholipase A2 Induces the Release of Proangiogenic and Antiangiogenic Factors by Human Neutrophils

Secreted phospholipases A2 (sPLA2s) are extracellular enzymes that catalyze the release of free fatty acids and lysophospholipids from membrane phospholipids and also bind to different receptors (e.g., PLA2R1 or integrins). To date, 12 mammalian sPLA2s have been identified, which play a critical role in pathophysiological processes including inflammation and cancer. sPLA2s activate immune cells such as human neutrophils (PMNs) by enzymatic activity- or receptor-mediated mechanisms. In addition, human PMNs synthesize and store human group V (hGV) and human group X (hGX) sPLA2s in their granules, but only the former is released upon cellular activation. We investigated the effects of sPLA2s on the release of proangiogenic and antiangiogenic factors by PMNs. We found that exogenous hGV and hGX sPLA2s induce the release of vascular endothelial growth factor (VEGF)-A, angiopoietin 1 (Ang1), and CXCL8/IL-8. Only hGV induces the secretion of the antiangiogenic isoform of VEGF-A, namely, VEGF-A165b. While the release of VEGF-A, Ang1, and CXCL8/IL-8 was likely mediated by hGV enzymatic activity and/or binding to PLA2R1 and heparan sulfate proteoglycans, the release of VEGF-A165b requires the interaction with αVβ3 and α4β1 integrins. We also provide evidence that endogenous hGV released by N-formyl-met-leu-phe (fMLF)-activated PMNs is involved in the release of angiogenic factors. The translational relevance of these data is supported by our findings that hGV expression is increased in human samples of lung cancer which are infiltrated by PMNs. Overall, our results suggest that the hGV-neutrophil axis may play a relevant role in the modulation of cancer-related inflammation and angiogenesis

Antiviral Activity of Vitis vinifera Leaf Extract against SARS-CoV-2 and HSV-1

Vitis vinifera represents an important and renowned source of compounds with significant biological activity. Wines and winery bioproducts, such as grape pomace, skins, and seeds, are rich in bioactive compounds against a wide range of human pathogens, including bacteria, fungi, and viruses. However, little is known about the biological properties of vine leaves. The aim of this study was the evaluation of phenolic composition and antiviral activity of Vitis vinifera leaf extract against two human viruses: the Herpes simplex virus type 1 (HSV-1) and the pandemic and currently widespread severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). About 40 phenolic compounds were identified in the extract by HPLC-MS/MS analysis: most of them were quercetin derivatives, others included derivatives of luteolin, kaempferol, apigenin, isorhamnetin, myricetin, chrysoeriol, biochanin, isookanin, and scutellarein. Leaf extract was able to inhibit both HSV-1 and SARS-CoV-2 replication in the early stages of infection by directly blocking the proteins enriched on the viral surface, at a very low concentration of 10 μg/mL. These results are very promising and highlight how natural extracts could be used in the design of antiviral drugs and the development of future vaccines

Effective Neutralizing Antibody Response Against SARS-CoV-2 Virus and Its Omicron BA.1 Variant in Fully Vaccinated Hematological Patients

SARS-CoV-2 and its variants cause CoronaVIrus Disease 19 (COVID-19), a pandemic disease. Hematological malignancies increase susceptibility to severe COVID-19 due to immunosuppression. Anti-SARS-CoV-2 neutralizing antibodies protect against severe COVID-19. This retrospective real-life study aimed to evaluate seropositivity and neutralizing antibody rates against SARS-CoV-2 and its Omicron BA.1 variant in hematological patients. A total of 106 patients with different hematologic malignancies, who have mostly received three or more vaccine doses (73%), were included in this study. Serum was collected between May and June 2022. The primary endpoint was anti-SARS-CoV-2 antibody response against ancestral (wild type; wt) and Omicron BA.1 virus, defined as a neutralizing antibody titer ≥ 1:10. Adequate neutralizing antibody response was observed in 75 (71%) and 87 (82%) of patients for wt and Omicron BA.1 variants, respectively.However, patients with B-cell lymphoproliferative disorders and/or those treated with anti-CD20 monoclonal antibodies in the prior 12 months showed a lower seropositivity rate compared to other patients against both Omicron BA.1 variant (73% vs 91%; P = 0.02) and wt virus (64% vs 78%; P = 0.16). Our real-life experience confirmed that full vaccination against SARS-CoV-2 induces adequate neutralizing antibody protection for both the wt virus and Omicron BA.1 variants, even in hematological frail patients. However, protective measures should be maintained in hematological patients, especially those with B-cell lymphoproliferative diseases treated with anti-CD20 monoclonal antibodies, because these subjects could have a reduced neutralizing antibody production

Microbiota and HPV: The role of viral infection on vaginal microbiota

The World Health Organization (WHO) estimates that the prevalence of human papillomaviruses (HPV) infection is between 9% and 13% of the world population and only in the United States, more than 6.2 million are positive every year. There are more than 100 types of HPV, among them, two serotypes (16 and 18) are related to 70% of cervical cancers and precancerous cervical lesions. The vaginal microbiota could play a considerable role in HPV infection and the genesis of cervical tumors caused by HPV. Moreover, bacteria are strongly associated with vaginal inflammation and oncogenic mutations in human cells. We aim to investigate whether HPV infection could influence the bacterial microbiota composition in the uterine cervix. A total of 31 women were enrolled in this study. The vaginal swabs were collected; the HPV-DNA was extracted with QIAamp DNA Microbiome. The V3-V4-V6 region of the 16S rDNA gene was amplified by polymerase chain reaction (PCR) followed by sequencing with MiSeq Illumina. The main phylum identified in the vaginal microbiota were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. The phylum of Actinobacteria, Proteobacteria, and Bacteroides was more represented in HPV-positive patients. Lactobacilli represented the dominant genus, with a high percentage of Lactobacilli iners, Lactobacilli jensenii, and Lactobacilli crispatus as species. Gardnerella vaginalis, Enterococcus spp., Staphylococcus spp., Proteus spp., and Atopobium were the most represented in HPV-positive patients. An altered vaginal microbiota might play a functional role in HPV cervical infection, progression, and clearance. The relationship between infection and microbiota could spur the development of new probiotics. However, further studies are needed to clarify the role of the vaginal microbiota in HPV infection

HIV and Drug-Resistant Subtypes

Acquired Immunodeficiency Syndrome (AIDS) is a human viral infectious disease caused by the positive-sense single-stranded (ss) RNA Human Immunodeficiency Virus (HIV) (Retroviridae family, Ortervirales order). HIV-1 can be distinguished into various worldwide spread groups and subtypes. HIV-2 also causes human immunodeficiency, which develops slowly and tends to be less aggressive. HIV-2 only partially homologates to HIV-1 despite the similar derivation. Antiretroviral therapy (ART) is the treatment approved to control HIV infection, based on multiple antiretroviral drugs that belong to different classes: (i) NNRTIs, (ii) NRTIs, (iii) PIs, (iv) INSTIs, and (v) entry inhibitors. These drugs, acting on different stages of the HIV life cycle, decrease the patient’s total burden of HIV, maintain the function of the immune system, and prevent opportunistic infections. The appearance of several strains resistant to these drugs, however, represents a problem today that needs to be addressed as best as we can. New outbreaks of strains show a widespread geographic distribution and a highly variable mortality rate, even affecting treated patients significantly. Therefore, novel treatment approaches should be explored. The present review discusses updated information on HIV-1– and HIV-2–resistant strains, including details on different mutations responsible for drug resistance

Casein-derived peptides from the dairy product kashk exhibit wound healing properties and antibacterial activity against Staphylococcus aureus: Structural and functional characterization

Kashk is a fermented dairy product typical of the Middle East, traditionally produced with sour milk and/or dairy waste. The kashk water-soluble peptide fraction was characterized at the molecular level by liquid chromatography-mass spectrometry and its antibacterial and skin healing activity was evaluated. Antibacterial assays showed a significant antibacterial activity against clinical isolates of Staphylococcus aureus (S. aureus) from patients with atopic dermatitis, inhibiting bacterial growth by approximately 45% (500 μg/mL). Skin repair activity was evaluated on keratinocytes through scratch tests showing accelerated wound closure in vitro in the presence of TNF-α, by approximately 44% (500 μg/mL), compared to control cells. Furthermore, based on the MTT assay, the kashk peptide fraction did not show toxicity on keratinocytes. The results suggested that the peptide kashk extract may be useful in skin care for patients with atopic dermatitis

Complete disappearance of a GH-secreting pituitary macroadenoma in a patient with acromegaly: effect of treatment with lanreotide Autogel and consequence of treatment withdrawal.

BACKGROUND: Somatostatin analogs (SA) are the cornerstone in the medical treatment of acromegaly, used as either primary or adjunctive therapy. In particular, SA are effective in inducing the biochemical remission of the disease and tumor shrinkage, although only few cases of complete disappearance of the pituitary tumor in patients treated with SA as long-acting formulations have been reported. SA withdrawal has been demonstrated to keep safe levels of GH and IGF1 at least in a small subset of patients well responsive to SA, although it is generally followed by disease recurrence after several months. CASE REPORT: A 61-year-old female patient bearing a very large GH-secreting pituitary macroadenoma was treated with 12-month lanreotide Autogel (ATG), at the initial dose of 120 mg/28 days. After 3 months, GH and IGF1 levels were fully normalized, to prolong the administration interval from 28 to 56 days. After 6 months of treatment, a significant tumor shrinkage (90% of baseline size) was observed, whereas GH and IGF1 excess was still well controlled. After 12-month therapy, a complete disappearance of the pituitary tumor was observed, and the hormonal evaluation confirmed the complete biochemical remission of acromegaly. Lanreotide ATG treatment was withdrawn. The clinical, biochemical, and radiological remission of acromegaly was maintained 24 months after lanreotide ATG treatment discontinuation, without evidence of disease recurrence. CONCLUSIONS: This report represents an exemplary case of the potentiality of treatment with lanreotide ATG in inducing a complete remission of acromegalic disease, persistent after a long period of time from treatment withdrawal

Prevalence and Antimicrobial Resistance of Causative Agents to Ocular Infections

Bacterial ocular infections are a worldwide health problem and, if untreated, can damage the structure of the eye and contribute to permanent disability. Knowledge of the prevalence and antimicrobial susceptibility patterns of the main causative agents involved in ocular infections is necessary for defining an optimal antibiotic therapy. The aim of this study was to analyse bacterial species involved in ocular infections and the antimicrobial susceptibility patterns. Conjunctival swab samples were collected from patients with bacterial conjunctivitis at the University Hospital San Giovanni di Dio e Ruggi d’Aragona between January 2015 and December 2019. The identification and antibiotic sensitivity tests were performed using the VITEK 2 system. A total of 281 causative agents of ocular infections were isolated, 81.8% of which were Gram-positive bacteria. Coagulase-negative staphylococci (CoNS) were the most commonly isolated species among Gram-positive bacteria, followed by Staphylococcus aureus. In contrast, Pseudomonas spp. and Escherichia coli were the main species isolated among Gram-negative bacteria (18.2%). Overall, linezolid, teicoplanin, tigecycline and vancomycin were the most effective antimicrobials. Analysis of resistance rates over time highlighted increasing resistance for azithromycin, clarithromycin and erythromycin among CoNS, and clindamycin and erythromycin among Staphylococcus aureus. This study has identified the profiles of the major pathogens involved in ocular infection and their susceptibility patterns, which will help improve the treatments and the choice of antibiotics in ocular infections