scholarly journals Repurposing Eltrombopag for Multidrug Resistant Staphylococcus aureus Infections

Antibiotics ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1372
Author(s):  
Hyunjung Lee ◽  
Jaehoan Lee ◽  
Juchan Hwang ◽  
Sinyoung Park ◽  
Namyoul Kim ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Aureus Strain ◽  
Infection Model ◽  
Cell Infection ◽  
Anaplastic Lymphoma ◽  
New Antibiotics ◽  
A Cell ◽  
Approved Drugs

The continuous rise of antimicrobial resistance urgently demands new therapeutic agents for human health. Drug repurposing is an attractive strategy that could significantly save time delivering new antibiotics to clinics. We screened 182 US Food and Drug Administration (FDA)-approved drugs to identify potential antibiotic candidates against Staphylococcus aureus, a major pathogenic bacterium. This screening revealed the significant antibacterial activity of three small molecule drugs against S. aureus: 1) LDK378 (Ceritinib), an anaplastic lymphoma kinase (ALK) inhibitor for the treatment of lung cancer, 2) dronedarone HCl, an antiarrhythmic drug for the treatment of atrial fibrillation, and 3) eltrombopag, a thrombopoietin receptor agonist for the treatment of thrombocytopenia. Among these, eltrombopag showed the highest potency against not only a drug-sensitive S. aureus strain but also 55 clinical isolates including 35 methicillin-resistant S. aureus (Minimum inhibitory concentration, MIC, to inhibit 50% growth [MIC50] = 1.4−3.2 mg/L). Furthermore, we showed that eltrombopag inhibited bacterial growth in a cell infection model and reduced bacterial loads in infected mice, demonstrating its potential as a new antibiotic agent against S. aureus that can overcome current antibiotic resistance.

scholarly journals Diminished LcrV Secretion Attenuates Yersinia pseudotuberculosis Virulence

2007 ◽  
Vol 189 (23) ◽  
pp. 8417-8429 ◽  
Author(s):  
Jeanette E. Bröms ◽  
Matthew S. Francis ◽  
Åke Forsberg
Keyword(s):  
Type Iii Secretion ◽  
Yersinia Pseudotuberculosis ◽  
Signal Sequence ◽  
Infection Model ◽  
Target Cells ◽  
Cell Infection ◽  
Host Cell Membrane ◽  
Type Iii ◽  
A Cell

ABSTRACT Many gram-negative bacterial pathogenicity factors that function beyond the outer membrane are secreted via a contact-dependent type III secretion system. Two types of substrates are predestined for this mode of secretion, namely, antihost effectors that are translocated directly into target cells and the translocators required for targeting of the effectors across the host cell membrane. N-terminal secretion signals are important for recognition of the protein cargo by the type III secretion machinery. Even though such signals are known for several effectors, a consensus signal sequence is not obvious. One of the translocators, LcrV, has been attributed other functions in addition to its role in translocation. These functions include regulation, presumably via interaction with LcrG inside bacteria, and immunomodulation via interaction with Toll-like receptor 2. Here we wanted to address the significance of the specific targeting of LcrV to the exterior for its function in regulation, effector targeting, and virulence. The results, highlighting key N-terminal amino acids important for LcrV secretion, allowed us to dissect the role of LcrV in regulation from that in effector targeting/virulence. While only low levels of exported LcrV were required for in vitro effector translocation, as deduced by a cell infection assay, fully functional export of LcrV was found to be a prerequisite for its role in virulence in the systemic murine infection model.

scholarly journals Fluorocycline TP-271 Is Potent against Complicated Community-Acquired Bacterial Pneumonia Pathogens

mSphere ◽  
2017 ◽  
Vol 2 (1) ◽  
Author(s):  
Trudy H. Grossman ◽  
Corey Fyfe ◽  
William O’Brien ◽  
Meredith Hackel ◽  
Mary Beth Minyard ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Bacterial Pneumonia ◽  
The Elderly ◽  
Multidrug Resistant ◽  
New Antibiotics ◽  
Severe Infections ◽  
Intravenous And Oral Administration ◽  
Resistance Rates

ABSTRACT Rising resistance rates for macrolides, fluoroquinolones, and β-lactams in the most common pathogens associated with community-acquired bacterial pneumonia (CABP) are of concern, especially for cases of moderate to severe infections in vulnerable populations such as the very young and the elderly. New antibiotics that are active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus are needed for use in the empirical treatment of the most severe forms of this disease. TP-271 is a promising new fluorocycline antibiotic demonstrating in vitro potency and nonclinical efficacy by intravenous and oral administration against the major pathogens associated with moderate to severe CABP. TP-271 is a novel, fully synthetic fluorocycline antibiotic in clinical development for the treatment of respiratory infections caused by susceptible and multidrug-resistant pathogens. TP-271 was active in MIC assays against key community respiratory Gram-positive and Gram-negative pathogens, including Streptococcus pneumoniae (MIC90 = 0.03 µg/ml), methicillin-sensitive Staphylococcus aureus (MSSA; MIC90 = 0.25 µg/ml), methicillin-resistant S. aureus (MRSA; MIC90 = 0.12 µg/ml), Streptococcus pyogenes (MIC90 = 0.03 µg/ml), Haemophilus influenzae (MIC90 = 0.12 µg/ml), and Moraxella catarrhalis (MIC90 ≤0.016 µg/ml). TP-271 showed activity (MIC90 = 0.12 µg/ml) against community-acquired MRSA expressing Panton-Valentine leukocidin (PVL). MIC90 values against Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae were 0.004, 1, and 4 µg/ml, respectively. TP-271 was efficacious in neutropenic and immunocompetent animal pneumonia models, generally showing, compared to the burden at the start of dosing, ~2 to 5 log10 CFU reductions against MRSA, S. pneumoniae, and H. influenzae infections when given intravenously (i.v.) and ~1 to 4 log10 CFU reductions when given orally (p.o.). TP-271 was potent against key community-acquired bacterial pneumonia (CABP) pathogens and was minimally affected, or unaffected, by tetracycline-specific resistance mechanisms and fluoroquinolone or macrolide drug resistance phenotypes. IMPORTANCE Rising resistance rates for macrolides, fluoroquinolones, and β-lactams in the most common pathogens associated with community-acquired bacterial pneumonia (CABP) are of concern, especially for cases of moderate to severe infections in vulnerable populations such as the very young and the elderly. New antibiotics that are active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus are needed for use in the empirical treatment of the most severe forms of this disease. TP-271 is a promising new fluorocycline antibiotic demonstrating in vitro potency and nonclinical efficacy by intravenous and oral administration against the major pathogens associated with moderate to severe CABP.

scholarly journals Simulated Antibiotic Exposures in anIn VitroHollow-Fiber Infection Model Influence Toxin Gene Expression and Production in Community-Associated Methicillin-Resistant Staphylococcus aureus Strain MW2

2011 ◽  
Vol 56 (1) ◽  
pp. 140-147 ◽  
Author(s):  
Solen Pichereau ◽  
Madhulatha Pantrangi ◽  
William Couet ◽  
Cedric Badiou ◽  
Gerard Lina ◽  
...  
Keyword(s):  
Gene Expression ◽  
Staphylococcus Aureus ◽  
Hollow Fiber ◽  
Aureus Strain ◽  
Enzyme Linked Immunosorbent Assay ◽  
Infection Model ◽  
Toxin Gene ◽  
Polymorphonuclear Cells ◽  
Methicillin Resistant

ABSTRACTCommunity-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) strain MW2 harbors a plethora of toxins to mediate its virulence. However, toxin expression and regulation with simulated clinical antimicrobial exposures are unclear. This study evaluated these relationships using anin vitropharmacodynamic hollow-fiber infection model. Clinical doses of clindamycin, linezolid, minocycline, trimethoprim-sulfamethoxazole (SXT), and vancomycin were simulated over 72 h against MW2 in the hollow fiber model. Expression levels oflukSF-PVand enterotoxin genessec4,sek,seq, andsel2were quantified by real-time PCR. Panton-Valentine leukocidin (PVL) was quantified by enzyme-linked immunosorbent assay (ELISA), and cytotoxicity was determined on polymorphonuclear cells (PMNs). Vancomycin produced the maximum MW2 killing (2.53 log10CFU/ml) after the first dose, but the greatest sustained killing over 72 h occurred with linezolid and clindamycin. Vancomycin and minocycline induced gene upregulation from 0 to 8 h, followed by downregulation for the remaining simulation period. Clindamycin decreased gene expression in the first 24 h, followed by moderate increases (2.5-fold) thereafter. Linezolid increased gene expression 11.4- to 200.4-fold but inhibited PVL production (0.6 ± 0.3 versus 5.9 ± 0.2 μg/ml, linezolid versus control at 72 h;P< 0.05). Similar effects on PVL production occurred with clindamycin and minocycline. SXT increased PVL production at 48 h (2.8-fold) and 72 h (4.9-fold) of treatment (P< 0.05), resulting in increased PVL cytotoxicity on PMNs. Linezolid, clindamycin, and minocycline were the most effective agents on decreasing the virulence potential in CA-MRSA, notably after 8 h of treatment. SXT had minimal effects on toxin gene regulation, but it increased production and cytotoxicity of PVL toxin in the model and may enhance virulence when it is used to treat severe infections.

scholarly journals Susceptibility of Ocular Staphylococcus aureus to Antibiotics and Multipurpose Disinfecting Solutions

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1203
Author(s):  
Madeeha Afzal ◽  
Ajay Kumar Vijay ◽  
Fiona Stapleton ◽  
Mark D. P. Willcox
Keyword(s):  
Staphylococcus Aureus ◽  
Contact Lens ◽  
Ocular Surface ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Aureus Strain ◽  
Microbial Keratitis ◽  
Significant Difference ◽  
Different Types ◽  
The Usa

Staphylococcus aureus is a frequent cause of ocular surface infections worldwide. Of these surface infections, those involving the cornea (microbial keratitis) are most sight-threatening. S. aureus can also cause conjunctivitis and contact lens-related non-infectious corneal infiltrative events (niCIE). The aim of this study was to determine the rates of resistance of S. aureus isolates to antibiotics and disinfecting solutions from these different ocular surface conditions. In total, 63 S. aureus strains from the USA and Australia were evaluated; 14 were from niCIE, 26 from conjunctivitis, and 23 from microbial keratitis (MK). The minimum inhibitory (MIC) and minimum bactericidal concentrations (MBC) of all the strains to ciprofloxacin, ceftazidime, oxacillin, gentamicin, vancomycin, chloramphenicol, azithromycin, and polymyxin B were determined. The MIC and MBC of the niCIE strains to contact lens multipurpose disinfectant solutions (MPDSs) was determined. All isolates were susceptible to vancomycin (100%). The susceptibility to other antibiotics decreased in the following order: gentamicin (98%), chloramphenicol (76%), oxacillin (74%), ciprofloxacin (46%), ceftazidime (11%), azithromycin (8%), and polymyxin B (8%). In total, 87% of all the isolates were multidrug resistant and 17% of the isolates from microbial keratitis were extensively drug resistant. The microbial keratitis strains from Australia were usually susceptible to ciprofloxacin (57% vs. 11%; p = 0.04) and oxacillin (93% vs. 11%; p = 0.02) compared to microbial keratitis isolates from the USA. Microbial keratitis isolates from the USA were less susceptible (55%) to chloramphenicol compared to conjunctivitis strains (95%; p = 0.01). Similarly, 75% of conjunctivitis strains from Australia were susceptible to chloramphenicol compared to 14% of microbial keratitis strains (p = 0.04). Most (93%) strains isolated from contact lens wearers were killed in 100% MPDS, except S. aureus 27. OPTI-FREE PureMoist was the most active MPDS against all strains with 35% of strains having an MIC ≤ 11.36%. There was a significant difference in susceptibility between OPTI-FREE PureMoist and Biotrue (p = 0.02). S. aureus non-infectious CIE strains were more susceptible to antibiotics than conjunctivitis strains and conjunctivitis strains were more susceptible than microbial keratitis strains. Microbial keratitis strains from Australia (isolated between 2006 and 2018) were more susceptible to antibiotics in comparison with microbial keratitis strains from the USA (isolated in 2004). Most of the strains were multidrug-resistant. There was variability in the susceptibility of contact lens isolates to MPDSs with one S. aureus strain, S. aureus 27, isolated from niCIE, in Australia in 1997 being highly resistant to all four MPDSs and three different types of antibiotics. Knowledge of the rates of resistance to antibiotics in different conditions and regions could help guide treatment of these diseases.

scholarly journals In vitro activity of hybrid lavender essential oils against multidrug resistant strains of Pseudomonas aeruginosa

2018 ◽  
Vol 12 (01) ◽  
pp. 009-014 ◽  
Author(s):  
Matthew Donadu ◽  
Donatella Usai ◽  
Antonio Pinna ◽  
Tiziana Porcu ◽  
Vittorio Mazzarello ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Essential Oils ◽  
Cell Model ◽  
Antimicrobial Properties ◽  
The United States ◽  
Multidrug Resistant ◽  
New Antibiotics ◽  
Mediterranean Regions ◽  
A Cell

Introduction: Lavender is an evergreen shrub native to Northern Africa and other mountainous Mediterranean regions. It grows throughout Southern Europe, the United States, and Australia. Lavender essential oil has been used since ancient times and is known for its anti-inflammatory, antidepressant, antiseptic, antifungal and antimicrobial properties. Methodology: in this study, the antimicrobial activity of two Lavender essential oils (Lavanda sumian and Lavanda grosso) against 16 multidrug-resistant P. aeruginosa strains from clinical ocular samples taken from migrant patients has been investigated. The in vitro cytotoxic activity on human Wong-Kilbourne derivative (WKD) conjunctiva cells from healthy patients and nitric oxide synthase (NOS) activity on murine macrophage (J774.1A) were also evaluated. Results: L. sumian showed lower antimicrobial activity when compared to L. grosso. Both lavender oils tested had no cytotoxic effect at very low concentrations, mostly L. grosso. The essential oils extracted from L. sumian and L. grosso significantly reduced NOS in a cell model. Conclusion: Increase in drug resistance and lack of new antibiotics may encourage the development of natural antimicrobial treatments.

scholarly journals Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

2021 ◽  
Vol 14 (10) ◽  
pp. 1051
Author(s):  
Onat Kadioglu ◽  
Mohamed Elbadawi ◽  
Edmond Fleischer ◽  
Thomas Efferth
Keyword(s):  
Drug Resistance ◽  
Molecular Docking ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Hek293 Cells ◽  
Transfected Cells ◽  
Anthracycline Resistance ◽  
Approved Drugs ◽  
Sensitizing Effect

Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA were overexpressed by lentiviral-plasmid-based transfection of HEK293 cells. An in silico drug repurposing approach was applied using virtual screening and molecular docking of FDA-approved drugs to identify inhibitors of these new drug-resistant genes. Overexpression of the selected genes conferred resistance to doxorubicin and daunorubicin but not to vincristine, docetaxel, and cisplatin, indicating the involvement of these genes in resistance to anthracyclines but not to a broader MDR phenotype. Using virtual drug screening and molecular docking analyses, we identified FDA-approved compounds (conivaptan, bexarotene, and desloratadine) that were interacting with HMOX1 and PRKCA at even stronger binding affinities than 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethenone and ellagic acid as known inhibitors of HMOX1 and PRKCA, respectively. Conivaptan treatment increased doxorubicin sensitivity of both HMOX1- and PRKCA-transfected cell lines. Bexarotene treatment had a comparable doxorubicin-sensitizing effect in HMOX1-transfected cells and desloratadine in PRKCA-transfected cells. Novel drug resistance mechanisms independent of ABC transporters have been identified that contribute to anthracycline resistance in MDR cells.

scholarly journals Complete Genome Sequence of Community-Acquired Methicillin-Resistant Staphylococcus aureus Strain RJ1267, Isolated in Shanghai, China

2020 ◽  
Vol 9 (18) ◽  
Author(s):  
Xianchun Zong ◽  
Dehua Liu ◽  
Min Li ◽  
Baolin Sun
Keyword(s):  
Staphylococcus Aureus ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Multidrug Resistant ◽  
Sequence Type ◽  
Aureus Strain ◽  
Methicillin Resistant ◽  
Content Type

Staphylococcal pathogens, especially multidrug-resistant Staphylococcus aureus, are responsible for various clinical infections. Multilocus sequence type 630 (ST630) methicillin-resistant Staphylococcus aureus has been shown to have augmented pathogenicity in humans. In this announcement, we report the complete genome sequence of community-acquired methicillin-resistant strain RJ1267 of Staphylococcus aureus ST630.

Indole and Indoline Scaffolds in Antimicrobials: Overview, Synthesis, and Recent Advances in Antimicrobial Research

2020 ◽  
Vol 27 ◽  
Author(s):  
Marcelo J. Nieto ◽  
Hannah K. Lupton
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Antibacterial Compounds ◽  
Disease States ◽  
New Antibiotics ◽  
Approved Drugs ◽  
Fda Approved Drugs

: In our current society, a pandemic of antibiotic-resistant infectious diseases is an ever-growing threat. The need for new antibiotics and ways to combat antibiotic resistance is glaring. This review will focus on two different privileged scaffolds, the indole and the indoline, as useful nuclei for novel antibacterial compounds. The indole, a moiety found in numerous approved drugs for many disease states, has recently been studied for its usefulness as a scaffold for compounds that have activity against antibiotic-resistant bacteria, especially against methicillin-resistant Staphylococcus aureus (MRSA). The indoline is a scaffold with significantly less historical studies and FDA-approved drugs and it has attracted new interest in drug design and development. In recent years, indoline-containing compounds have been shown to have antibacterial activity as well as activity as a resistance-modifying agent (RMA), which act to improve the effectiveness of current antibiotic therapies that have known resistance.

scholarly journals Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

Antibiotics ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 65 ◽  
Author(s):  
Olga Pacios ◽  
Lucia Blasco ◽  
Inès Bleriot ◽  
Laura Fernandez-Garcia ◽  
Mónica González Bardanca ◽  
...  
Keyword(s):  
Phage Therapy ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Recurrent Infections ◽  
International Crisis ◽  
New Antibiotics ◽  
Persistent Bacteria ◽  
Antibiotic Failure ◽  
Almost All

Antibiotic failure is one of the most worrying health problems worldwide. We are currently facing an international crisis with several problematic facets: new antibiotics are no longer being discovered, resistance mechanisms are occurring in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria are hampering the successful treatment of infections. In this context, new anti-infectious strategies against multidrug-resistant (MDR) and persistent bacteria, as well as the rescue of Food and Drug Administration (FDA)-approved compounds (drug repurposing), are being explored. Among the highlighted new anti-infectious strategies, in this review, we focus on antimicrobial peptides, anti-virulence compounds, phage therapy, and new molecules. As drugs that are being repurposed, we highlight anti-inflammatory compounds, anti-psychotics, anti-helminthics, anti-cancerous drugs, and statins.

scholarly journals A Cell-Free Screen for Bacterial Membrane Disruptors Identifies Mefloquine as a Novel Antibiotic Adjuvant

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 315
Author(s):  
Jessica Podoll ◽  
Justin Olson ◽  
Wei Wang ◽  
Xiang Wang
Keyword(s):  
Staphylococcus Aureus ◽  
High Throughput ◽  
Antibiotic Activity ◽  
Bacterial Membrane ◽  
Bacterial Membranes ◽  
Hit Rate ◽  
New Antibiotics ◽  
Lactam Antibiotic ◽  
A Cell ◽  
Bacterial Model

Antibacterial discovery efforts have lagged far behind the need for new antibiotics. An approach that has gained popularity recently is targeting bacterial phospholipid membranes. We leveraged the differences between bacterial and mammalian phospholipid compositions to develop a high-throughput screen that identifies agents that selectively disrupt bacterial membranes while leaving mammalian membranes intact. This approach was used to screen 4480 compounds representing a subset of the Maybridge HitFinderTM V.11 Collection and the Prestwick Chemical Drug Library®. The screen identified 35 “positives” (0.8% hit rate) that preferentially damage bacterial model membranes. Among these, an antimalarial compound, mefloquine, and an aminoglycoside, neomycin, were identified. Further investigation of mefloquine’s activity against Staphylococcus aureus showed that it has little antibiotic activity on its own but can alter membrane fluidity, thereby potentiating a β-lactam antibiotic, oxacillin, against both methicillin-susceptible and methicillin-resistant S. aureus. This study indicates that our cell-free screening approach is a promising platform for discovering bacterial membrane disruptors as antibacterials antibiotic adjuvants.

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