Lipophilic Ga Complex with Broad-Spectrum Antimicrobial Activity and the Ability to Overcome Gallium Resistance in both Pseudomonas aeruginosa and Staphylococcus aureus.
Antibiotic resistance (AR) necessitates the discovery of new antimicrobials with alternative mechanisms of action to those employed by conventional antibiotics. One such strategy utilizes Ga(3+) to target iron metabolism, a critical process for survival. Still, Ga-based therapies are generally ineffective against Gram-positive bacteria and promote Ga resistance. In response to these drawbacks, we report a lipophilic Ga complex, [Ga(2)L(3)(bpy)(2)] (L = 2,2'-bis(3-hydroxy-1,4-naphthoquinone; bpy = 2,2'-bipyridine)), effective against drug-resistant Pseudomonas aeruginosa (DRPA; minimum inhibitory concentration, MIC = 10 μM = 14.8 μg/mL) and methicillin-resistant Staphylococcus aureus (MRSA, MIC = 100 μM = 148 μg/mL) without iron-limited conditions. Importantly, [Ga(2)L(3)(bpy)(2)] shows noticeably delayed and decreased resistance in both MRSA and DRPA, with only 8× MIC in DRPA and none in MRSA after 30 passages. This is likely due to the dual mode of action afforded by Ga (disruption of iron metabolism) and the ligand (reactive oxygen species production). Overall, [Ga(2)L(3)(bpy)(2)] demonstrates the utility of lipophilic metal complexes with multiple modes of action in combatting AR in Gram-positive and Gram-negative bacteria.
Wang Z; Li J; Benin BM;Yu B; Bunge Scott D; Abeydeera N; Huang SD; Kim M-H
Journal Of Medicinal Chemistry
2021
2021-06-17
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1021/acs.jmedchem.1c00656" target="_blank" rel="noreferrer noopener">10.1021/acs.jmedchem.1c00656</a>
Tissue-Specific Proteomics Analysis of Anti-COVID-19 Nucleoside and Nucleotide Prodrug-Activating Enzymes Provides Insights into the Optimization of Prodrug Design and Pharmacotherapy Strategy.
Nucleoside and nucleotide analogs are an essential class of antivirals for COVID-19 treatment. Several nucleoside/nucleotide analogs have shown promising effects against SARS-CoV-2 in vitro ; however, their in vivo efficacy is limited. Nucleoside/nucleotide analogs are often formed as ester prodrugs to improve pharmacokinetics (PK) performance. After entering cells, the prodrugs undergo several enzymatic metabolism steps to form the active metabolite triphosphate nucleoside (TP-Nuc); prodrug activation is therefore associated with the abundance and catalytic activity of the corresponding activating enzymes. Having the activation of nucleoside/nucleotide prodrugs occur at the target site of action, such as the lung, is critical for anti-SARS-CoV-2 efficacy. Herein, we conducted an absolute quantitative proteomics study to determine the expression of relevant activating enzymes in human organs related to the PK and antiviral efficacy of nucleoside/nucleotide prodrugs, including the lung, liver, intestine, and kidney. The protein levels of prodrug-activating enzymes differed significantly among the tissues. Using catalytic activity values reported previously for individual enzymes, we calculated prodrug activation profiles in these tissues. The prodrugs evaluated in this study include nine McGuigan phosphoramidate prodrugs, two cyclic monophosphate prodrugs, two l-valyl ester prodrugs, and one octanoate prodrug. Our analysis showed that most orally administered nucleoside/nucleotide prodrugs were primarily activated in the liver, suggesting that parenteral delivery routes such as inhalation and intravenous infusion could be better options when these antiviral prodrugs are used to treat COVID-19. The results also indicated that the l-valyl ester prodrug design can plausibly improve drug bioavailability and enhance effects against SARS-CoV-2 intestinal infections. This study further revealed that an octanoate prodrug could provide a long-acting antiviral effect targeting SARS-CoV-2 infections in the lung. Finally, our molecular docking analysis suggested several prodrug forms of favipiravir and GS-441524 that are likely to exhibit favorable PK features over existing prodrug forms. In sum, this study revealed the activation mechanisms of various nucleoside/nucleotide prodrugs relevant to COVID-19 treatment in different organs and shed light on the development of more effective anti-COVID-19 prodrugs. (© 2021 American Chemical Society.)
Li J; Liu S; Shi J; Wang X; Xue Y; Zhu H-J
Acs Pharmacology & Translational Science
2021
2021-04-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1021/acsptsci.1c00016" target="_blank" rel="noreferrer noopener">10.1021/acsptsci.1c00016</a>
Outcomes among patients with heart failure with reduced ejection fraction undergoing transcatheter aortic valve replacement: Minimally invasive strategy versus conventional strategy.
Female; Humans; Male; Aged; Retrospective Studies; Treatment Outcome; Prognosis; Cohort Studies; Severity of Illness Index; Aged 80 and over; Logistic Models; Survival Rate; Length of Stay; Multivariate Analysis; Risk Assessment; Reference Values; Hospital Mortality; aortic stenosis; transcatheter aortic valve replacement; heart failure; Transcatheter Aortic Valve Replacement/methods/mortality; anesthesia; conscious sedation; Aortic Valve Stenosis/diagnostic imaging/epidemiology/therapy; Cardiac Catheterization/methods; Cardiac Output Low/diagnostic imaging; Conscious Sedation/methods; Echocardiography Transesophageal/methods; Heart Failure/diagnosis/epidemiology/therapy; Minimally Invasive Surgical Procedures/methods; Surgery Computer-Assisted/methods
OBJECTIVES: To investigate the effect of TAVR technique on in-hospital and 30-day outcomes in patients with aortic stenosis (AS) and reduced ejection fraction (EF). BACKGROUND: Patients with AS and concomitant low EF may be at risk for adverse hemodynamic effects from general anesthesia utilized in transcatheter aortic valve replacement (TAVR) via the conventional strategy (CS). These patients may be better suited for the minimally invasive strategy (MIS), which employs conscious sedation. However, data are lacking that compare MIS to CS in patients with AS and concomitant low EF. METHODS: In this retrospective study, we identified all patients with low EF (<50%) undergoing transfemoral MIS-TAVR vs CS-TAVR between March 2011 and May 2018. Our primary endpoint was defined as the composite of in-hospital mortality and major periprocedural bleeding or vascular complications. RESULTS: Two hundred and seventy patients had EF <50%, while 154 patients had EF ≤35%. Overall, a total of 236 patients were in the MIS group and 34 were in the CS group. Baseline characteristics between the two groups were similar except for Society of Thoracic Surgeons (STS) score (MIS 8.4 ± 5.1 vs CS 11.7 ± 6.8; P<.01). There were no differences between the two groups in incidence of the primary endpoint (MIS 5.5% vs CS 8.8%; odds ratio for MIS, 0.60; 95% confidence interval, 0.16-2.23; P=.45). CONCLUSIONS: In patients with severe AS and reduced EF, MIS was not associated with adverse in-hospital or 30-day clinical outcomes compared with CS. In these patients, MIS may be a suitable alternative to CS without compromising clinical outcomes.
Panhwar MS; Li J; Zidar DA; Clevenger J; Lipinski J; Patel TR; Karim A; Saric P; Patel SM; Kalra A; Attizzani GF
The Journal of invasive cardiology
2019
2019-03
Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
journalArticle
<a href="http://doi.org/" target="_blank" rel="noreferrer noopener"></a>
PMID: 30555054
Short-term and long-term outcomes of patients undergoing urgent transcatheter aortic valve replacement under a minimalist strategy.
Female; Humans; Male; Retrospective Studies; Treatment Outcome; Risk Factors; United States/epidemiology; Follow-Up Studies; Severity of Illness Index; Time Factors; Aged 80 and over; Length of Stay; transcatheter aortic valve replacement; Transcatheter Aortic Valve Replacement/methods; minimalist approach; Hospital Mortality/trends; severe aortic stenosis; urgent procedure; Aortic Valve Stenosis/diagnosis/mortality/surgery; Aortic Valve/diagnostic imaging/surgery; Cardiac Catheterization/methods; Echocardiography Transesophageal; Elective Surgical Procedures/methods; Femoral Artery
OBJECTIVES: Urgent transcatheter aortic valve replacement (TAVR) is associated with worse short-term outcomes compared with elective TAVR; however, little is known about long-term outcomes or the safety of the minimalist strategy in this setting. This study investigated the short-term and long-term outcomes of urgent TAVR compared with elective TAVR under a minimalist strategy (transfemoral [TF] approach with conscious sedation and no transesophageal echocardiography guidance). METHODS: After excluding 2 emergent patients requiring immediate procedures, a total of 474 consecutive patients underwent elective TF-TAVR (396 patients; 83.6%) or urgent
Ichibori Y; Li J; Patel T; Lipinski J; Ladas T; Saric P; Kobe D; Tsushima T; Peters M; Patel S; Davis A; Markowitz AH; Bezerra HG; Costa MA; Kalra A; Attizzani GF
The Journal of invasive cardiology
2019
2019-02
Copyright © 2019 Elsevier Inc. All rights reserved.
journalArticle
<a href="http://doi.org/" target="_blank" rel="noreferrer noopener"></a>
PMID: 30700628
Feasibility and safety of adopting next-day discharge as first-line option after transfemoral transcatheter aortic valve replacement.
Female; Humans; Male; Aged; Retrospective Studies; Cohort Studies; Follow-Up Studies; Severity of Illness Index; Time Factors; United States; Aged 80 and over; Survival Analysis; Patient Readmission/statistics & numerical data; Propensity Score; Ohio; Academic Medical Centers; Risk Assessment; Feasibility Studies; Patient Discharge; aortic stenosis; transcatheter aortic valve replacement; Length of Stay; early discharge; minimalist approach; next-day discharge; Patient Safety; Aortic Valve Stenosis/diagnosis/surgery; Transcatheter Aortic Valve Replacement/methods/mortality
OBJECTIVES: Data on next-day discharge (NDD) after transcatheter aortic valve replacement (TAVR) are limited. This study investigated the feasibility and safety of NDD as a first-line option (the very-early discharge [VED] strategy) compared with the early-discharge (ED) strategy (2-3 days as a first-line option) after TAVR. METHODS: We reviewed 611 consecutive patients who had minimalist TAVR (transfemoral approach under conscious sedation) and no in-hospital mortality; a total of 418 patients underwent ED strategy (since December 2013) and 193 patients underwent VED strategy (as part of a hospital initiative to reduce length of stay, since August 2016). NDD in the VED strategy was performed with heart team consensus in patients without significant complications. The primary outcome was a composite of 30-day all-cause mortality/rehospitalization. RESULTS: Sixty-five patients (33.7%) in the VED strategy and 10 patients (2.4%) in the ED strategy were discharged the next day (P<.001). NDD patients had received balloon-expandable (n = 30) or self-expanding valves (n = 45) and showed a similar primary outcome rate compared with non-NDD patients. After adjustment using propensity score matching (172 pairs), post-TAVR length of stay was significantly shorter in the VED group (3.2 ± 3.1 days) than in the ED group (3.5 ± 2.7 days; P<.01). The primary outcome did not differ between the two groups (7.0% vs 11.6%; P=.14), with comparable 30-day mortality rate (1.2% vs 2.3%; P=.68) and rehospitalization rate (5.8% vs 11.1%; P=.08). CONCLUSIONS: Utilization of NDD as a first-line option after minimalist TAVR is feasible and safe, and leads to further reduction in length of stay compared with an ED strategy.
Ichibori Y; Li J; Davis A; Patel TM; Lipinski J; Panhwar M; Saric P; Qureshi G; Patel SM; Sareyyupoglu B; Markowitz AH; Bezerra HG; Costa MA; Zidar DA; Kalra A; Attizzani GF
The Journal of invasive cardiology
2019
2019-03
© 2019 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.
journalArticle
<a href="http://doi.org/" target="_blank" rel="noreferrer noopener"></a>
PMID: 30819977