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1.
Proc Natl Acad Sci U S A ; 121(17): e2322363121, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38640341

RESUMO

Anti-microbial resistance (AMR) is one of the greatest threats to global health. The continual battle between the emergence of AMR and the development of drugs will be extremely difficult to stop as long as traditional anti-biotic approaches are taken. In order to overcome this impasse, we here focused on the type III secretion system (T3SS), which is highly conserved in many Gram-negative pathogenic bacteria. The T3SS is known to be indispensable in establishing disease processes but not essential for pathogen survival. Therefore, T3SS inhibitors may be innovative anti-infective agents that could dramatically reduce the evolutionary selective pressure on strains resistant to treatment. Based on this concept, we previously identified a polyketide natural product, aurodox (AD), as a specific T3SS inhibitor using our original screening system. However, despite its promise as a unique anti-infective drug of AD, the molecular target of AD has remained unclear. In this paper, using an innovative chemistry and genetic biology-based approach, we show that AD binds to adenylosuccinate synthase (PurA), which suppresses the production of the secreted proteins from T3SS, resulting in the expression of bacterial virulence both in vitro and in vivo experiments. Our findings illuminate the potential of PurA as a target of anti-infective drugs and vaccination and could open a avenue for application of PurA in the regulation of T3SS.


Assuntos
Aurodox , Sistemas de Secreção Tipo III , Sistemas de Secreção Tipo III/metabolismo , Aurodox/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Bactérias Gram-Negativas/metabolismo , Proteínas de Bactérias/metabolismo
2.
Antimicrob Agents Chemother ; 68(7): e0026724, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38771029

RESUMO

The aim of this study was to analyze the population pharmacokinetics of total and unbound concentrations of prophylactic cefazolin (CFZ) in patients with prostatectomy or nephrectomy. We also aimed to calculate a pharmacodynamics target unbound concentration that exceeded the minimum inhibitory concentration (MIC), to design an effective dosing regimen. Briefly, 614 total concentration and 610 unbound concentration samples from 152 individuals were evaluated, using a nonlinear mixed-effects model. The obtained pharmacodynamics index target value reflected the probability of maintaining CFZ unbound trough concentrations exceeding MIC90, 0.5 mg/L, and MIC50, and 1.0 mg/L, to account for methicillin-susceptible Staphylococcus aureus (MSSA) or Escherichia coli. Population pharmacokinetics were estimated using a two-compartment model with nonlinear protein binding. Unbound systemic clearance (CL) was significantly associated with creatinine clearance, while the maximum protein-binding constant was significantly associated with albumin levels. The probability of achieving an unbound concentration exceeding the MIC50 for E. coli or MIC90 for MSSA in a patient with normal renal function following a 1 g CFZ infusion over 15 min was above 90% at 3 h after the initial dose. Our findings indicated that population pharmacokinetic parameters are useful for determining unbound CFZ pharmacokinetics and evaluating intraoperative CFZ redosing intervals.


Assuntos
Antibacterianos , Cefazolina , Escherichia coli , Testes de Sensibilidade Microbiana , Nefrectomia , Prostatectomia , Humanos , Cefazolina/farmacocinética , Cefazolina/sangue , Cefazolina/uso terapêutico , Masculino , Antibacterianos/farmacocinética , Antibacterianos/sangue , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Pessoa de Meia-Idade , Idoso , Feminino , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Adulto , Ligação Proteica , Idoso de 80 Anos ou mais
3.
Antimicrob Agents Chemother ; : e0160223, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38709005

RESUMO

KSP-1007 is a novel bicyclic boronate-based broad-spectrum ß-lactamase inhibitor and is being developed in combination with meropenem (MEM) for the treatment of infections caused by carbapenem-resistant Gram-negative bacteria, a global health concern, and here, we describe its characteristics. KSP-1007 exhibited low apparent inhibition constant (Ki app) values against all classes of ß-lactamase, including imipenemase types and oxacillinase types from Acinetobacter baumannii. Against 207 Enterobacterales and 55 A. baumannii, including carbapenemase producers, KSP-1007 at fixed concentrations of 4, 8, and 16 µg/mL dose-dependently potentiated the in vitro activity of MEM in broth microdilution MIC testing. The MIC90 of MEM/KSP-1007 at 8 µg/mL against Enterobacterales was lower than those of MEM/vaborbactam, ceftazidime/avibactam, imipenem/relebactam, and colistin and similar to those of aztreonam/avibactam, cefiderocol, and tigecycline. The in vitro activity of MEM/KSP-1007 at ≥4 µg/mL against Enterobacterales harboring metallo-ß-lactamase was superior to that of cefepime/taniborbactam. MEM/KSP-1007 showed excellent activity against Escherichia coli with PBP3 mutations and New Delhi metallo-ß-lactamase compared to aztreonam/avibactam, cefepime/taniborbactam, and cefiderocol. MEM/KSP-1007 at 8 µg/mL showed greater efficacy against A. baumannii than these comparators except for cefiderocol, tigecycline, and colistin. A 2-fold reduction in MEM MIC against 96 Pseudomonas aeruginosa was observed in combination with KSP-1007. MEM/KSP-1007 demonstrated bactericidal activity against carbapenemase-producing Enterobacterales, A. baumannii, and P. aeruginosa based on minimum bactericidal concentration/MIC ratios of ≤4. KSP-1007 enhanced the in vivo activity of MEM against carbapenemase-producing Enterobacterales, A. baumannii, and P. aeruginosa in murine systemic, complicated urinary tract, and thigh infection models. Collectively, MEM/KSP-1007 has a good profile for treating carbapenem-resistant Gram-negative bacterial infections.

4.
J Nat Prod ; 87(5): 1459-1470, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38652684

RESUMO

Actinomycetes are prolific producers of natural products, particularly antibiotics. However, a significant proportion of its biosynthetic gene clusters (BGCs) remain silent under typical laboratory conditions. This limits the effectiveness of conventional isolation methods for the discovery of novel natural products. Genetic interventions targeting the activation of silent gene clusters are necessary to address this challenge. Streptomyces antibiotic regulatory proteins (SARPs) act as cluster-specific activators and can be used to target silent BGCs for the discovery of new antibiotics. In this study, the expression of a previously uncharacterized SARP protein, Syo_1.56, in Streptomyces sp. RK18-A0406 significantly enhanced the production of known antimycins and led to the discovery of 12 elasnins (1-12), 10 of which were novel. The absolute stereochemistry of elasnin A1 was assigned for the first time to be 6S. Unexpectedly, Syo_1.56 seems to function as a pleiotropic rather than cluster-specific SARP regulator, with the capability of co-regulating two distinct biosynthetic pathways, simultaneously. All isolated elasnins were active against wild-type and methicillin-resistant Staphylococcus aureus with IC50 values of 0.5-20 µg/mL, some of which (elasnins A1, B2, and C1 and proelasnins A1, and C1) demonstrated moderate to strong antimalarial activities against Plasmodium falciparum 3D7. Elasnins A1, B3, and C1 also showed in vitro inhibition of the metallo-ß-lactamase responsible for the development of highly antibiotic-resistant bacterial strains.


Assuntos
Antibacterianos , Streptomyces , Antibacterianos/farmacologia , Antibacterianos/química , Streptomyces/química , Streptomyces/genética , Família Multigênica , Testes de Sensibilidade Microbiana , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Estrutura Molecular , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos
5.
Biosci Biotechnol Biochem ; 88(10): 1242-1246, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39025804

RESUMO

We envisioned that the rumen of Kitasato Yakumo beef cattle would contain unique microorganisms which produce bioactive compounds as their defense response to the external environment. The variety of microorganisms were collected from the feces of Kitasato Yakumo beef cattle. We evaluated the biological activity of the culture broth of the isolated strains, proving the utility of our approach.


Assuntos
Produtos Biológicos , Fezes , Animais , Bovinos , Fezes/microbiologia , Produtos Biológicos/isolamento & purificação , Bactérias/classificação , RNA Ribossômico 16S/genética
6.
J Infect Chemother ; 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39197667

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health threat. Although several effective vaccines and therapeutics have been developed, continuous emergence of new variants necessitates development of drugs with different mechanisms of action. Recent studies indicate that cepharanthine, a chemical derivative purified from Stephania cepharantha, inhibits SARS-CoV-2 replication in vitro. METHODS: This study examined the in vivo effects of cepharanthine using a Syrian hamster SARS-CoV-2 infection model. To evaluate the prophylactic and therapeutic effects, cepharanthine was intranasally administered before or after SARS-CoV-2 infection. Effects were assessed by monitoring body weight changes, lung pathology, lung viral load, and inflammatory response in the lungs. RESULTS: Pre-infection administration of cepharanthine resulted in less weight loss, reduced virus titers, alleviated histopathological severity, and decreased lung inflammation. Furthermore, post-infection administration of cepharanthine also exhibited therapeutic effects. CONCLUSIONS: This study demonstrated that both prophylactic and therapeutic administration of cepharanthine reduces the pathogenesis of COVID-19 in a Syrian hamster SARS-CoV-2 infection model. Our findings suggest that cepharanthine is a potential therapeutic agent against COVID-19.

7.
J Infect Chemother ; 30(4): 315-322, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37940039

RESUMO

BACKGROUND: Clarifying the presence of viable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rather than SARS-CoV-2 viral RNA in inpatient rooms is important for infection control of coronavirus disease 2019 (COVID-19). In this study, we investigated levels of viral RNA and viable virus on environmental surfaces and in patient saliva. METHODS: Environmental samples from 23 sites in hospital rooms were collected every other day until patient discharge. Saliva specimens and samples from the inner surface of patient masks were also collected. Additionally, environmental samples were collected from 46 sites in hospital rooms on discharge day. The samples were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and plaque assays. RESULTS: The 10 enrolled cases were classified as mild COVID-19, and patients were discharged after 6-9 days. The viral RNA was detected in 12.4% (105/849) of serially collected environmental samples during hospitalization, whereas viable virus was detected only in 0.47% (4/849), which were from sinks and tap levers. Although all patients recovered, three cases retained viable virus in the last saliva specimen collected. In the 15 discharged rooms, viral RNA was detected in 6.6% (45/682) of the samples, and viable virus was detected in only one sample from the sink. CONCLUSIONS: Although environmental surfaces surrounding patients with COVID-19 were frequently contaminated with viral RNA, the presence of viable virus was rare and limited only to areas around sinks. These results suggest that contact infection risk via fomites in hospital rooms is extremely rare.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Carga Viral , Hospitais , RNA Viral
8.
J Water Health ; 22(3): 601-611, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38557574

RESUMO

Coronavirus disease 2019 (COVID-19) is an infectious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged at the end of 2019. SARS-CoV-2 can be transmitted through droplets, aerosols, and fomites. Disinfectants such as alcohol, quaternary ammonium salts, and chlorine-releasing agents, including hypochlorous acid, are used to prevent the spread of SARS-CoV-2 infection. In the present study, we investigated the efficacy of ionless hypochlorous acid water (HOCl) in suspension and by spraying to inactivate SARS-CoV-2. The virucidal efficacy of HOCl solution in tests against SARS-CoV-2 was evaluated as 50% tissue culture infectious dose. Although the presence of organic compounds influenced the virucidal efficacy, HOCl treatment for 20 s was significantly effective to inactivate Wuhan and Delta strains in the suspension test. HOCl atomization for several hours significantly reduced the SARS-CoV-2 attached to plastic plates. These results indicate that HOCl solution with elimination containing NaCl and other ions may have high virucidal efficacy against SARS-CoV-2. This study provides important information about the virucidal efficacy and use of HOCl solution.


Assuntos
COVID-19 , Desinfetantes , Humanos , SARS-CoV-2 , COVID-19/prevenção & controle , Ácido Hipocloroso/farmacologia , Água , Desinfetantes/farmacologia
9.
Chem Biodivers ; 21(2): e202301834, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38179845

RESUMO

We discovered a new tetronomycin analog, C-32-OH tetronomycin (2) from the Streptomyces sp. K20-0247 strain, which produces tetronomycin (1). After NMR analysis of 2, we determined the planar structure. Futhermore, the absolute stereochemistry of 2 was deduced based on the biosynthetic pathway of 1 in the K20-0247 strain and a comparison of experimental electronic circular dichroism (ECD) results of 1 with 2. While 2 exihibits potent antibacterial activity aganist Gram-positive baceria including vancomycin-intermediate Staphylococcus aureus (VISA) strains and vancomycin-resistant Enterococci (VRE), the antibacterial activity of 2 shows 16-32-folds weaker than that of 1 suggesting that the C-34 methyl group in 1 is one of the very important functinal group. Moreover, we evaluated the ionophore activity of 1 and 2 and neither compound shows ionophore activity at reasonable concetrations. Our research suggests that 1 and 2 would have different target(s) from an ionophore mechanism in the antibacterial activity and tetronomycins are promising natural products for broad-spectrum antibiotics.


Assuntos
Antibacterianos , Éteres , Antibacterianos/farmacologia , Bactérias Gram-Positivas , Ionóforos , Testes de Sensibilidade Microbiana
10.
Bioorg Med Chem ; 78: 117109, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36603397

RESUMO

3Z,5E-Octa-3,5-diene-1,3,4-tricarboxylic acid-3,4-anhydride (ODTAA, 1) was isolated from Paecilomyces sp. FKI-6801 for its selective IMP-1 MBL inhibitory activity. The first total synthesis of 1 from the commercially available compound was achieved in 9 steps with 28% overall yield. Introduction of catechol to the maleic anhydride of 1 improved the IC50 toward IMP-1 MBL and the inhibitory activity against IMP-1 MBL-producing P. aeruginosa. Treatment of the maleic anhydride scaffold with amine showed that the ß-carbonyl-α,ß-unsaturated carboxylic acid moiety is required as a pharmacophore for IMP-1 MBL inhibition.


Assuntos
Infecções por Pseudomonas , Humanos , Anidridos , Anidridos Maleicos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa , beta-Lactamases , Antibacterianos/farmacologia
11.
Jpn J Clin Oncol ; 53(12): 1201-1207, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-37681230

RESUMO

OBJECTIVE: Adenosquamous carcinoma of the lung is a characteristic tumor that has both adenocarcinoma and squamous cell carcinoma components. Adenosquamous carcinoma is reported to have an aggressive clinical course, but its clinicopathological features and prognosis are unclear in the early stage. METHODS: Patients who underwent surgical resection for pathological stage I non-small cell lung cancer between April 2009 and December 2014 were retrospectively reviewed. Preoperative and postoperative data, histologic characteristics and outcomes of patients with adenosquamous carcinoma (n = 40) were compared to adenocarcinoma (n = 598) and squamous cell carcinoma (n = 131) patients. Factors affecting prognosis, particularly on recurrence, were assessed via Cox regression analyses. RESULTS: Patients with adenosquamous carcinoma had a worse prognosis than did patients with adenocarcinoma and squamous cell carcinoma in terms of 5 year overall (66.7%) and recurrence-free survival rates (44.9%), as well as a significantly higher recurrence rate (13/40 patients, 32.5%). Multivariable Cox regression analysis for recurrence-free survival rates revealed that the histology of adenosquamous carcinoma was an independent factor for recurrence (hazard ratio: 2.473, 95% confidence interval: 1.328-3.367; P = 0.0004). High serum carcinoembryonic antigen levels (hazard ratio: 5.962) and vascular invasion (hazard ratio: 4.899) were identified as risk factors for recurrence, and patients with adenosquamous carcinoma tended to have distant relapses, such as in the brain. CONCLUSIONS: Early-stage adenosquamous carcinoma of the lung is a histological type associated with severe prognosis and postoperative recurrence, often in distant sites, in approximately one-third of cases. High serum carcinoembryonic antigen levels and vascular invasion might be risk factors of recurrence.


Assuntos
Adenocarcinoma , Carcinoma Adenoescamoso , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma Adenoescamoso/cirurgia , Estadiamento de Neoplasias , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos Retrospectivos , Antígeno Carcinoembrionário , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Carcinoma de Células Escamosas/patologia , Adenocarcinoma/patologia , Pulmão/patologia
12.
J Infect Chemother ; 29(5): 481-484, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36736701

RESUMO

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infection is one of the most difficult infections we have to treat. Linezolid is one of the effective treatment options for refractory MRSA infections. There are cases where we are forced to use long-term linezolid treatment for refractory MRSA infections. OBJECTIVE: To discuss the evolution of Linezolid resistance factors in clinical isolates of MRSA. METHODS: We investigated 16 MRSA isolated from a patient treated with linezolid for a long period of 75 days. We performed antibiotic susceptibility test, 23S rRNA genes sequencing analysis, Pulsed-field gel electrophoresis. RESULTS: MRSA isolates were susceptible to linezolid before the start of treatment, but became less susceptible by prolonged treatment. The 23S rRNA sequencing analysis of linezolid-resistant strains that appeared 17 days after the start of treatment with linezolid revealed that all resistant MRSA had the G2576T substitution (Escherichia coli 23S rRNA gene number). The number of copies of this mutation increased with the use of linezolid. CONCLUSION: Long-term use of linezolid in a patient or reuse of linezolid in a patient who has been previously treated with linezolid can lead to the emerging of linezolid-resistant MRSA in the host.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Linezolida/farmacologia , Linezolida/uso terapêutico , Genes de RNAr , RNA Ribossômico 23S/genética , Mutação Puntual , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Variações do Número de Cópias de DNA , Infecções Estafilocócicas/tratamento farmacológico , Farmacorresistência Bacteriana/genética , Testes de Sensibilidade Microbiana
13.
J Infect Chemother ; 29(6): 604-609, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36894016

RESUMO

BACKGROUND: Although crowds are considered to be a risk factor for SARS-CoV-2 transmission, little is known about the changes in environmental surface contamination with the virus when a large number of people attend an event. In this study, we evaluated the changes in environmental surface contamination with SARS-CoV-2. METHODS: Environmental samples were collected from concert halls and banquet rooms before and after events in February to April 2022 when the 7-day moving average of new COVID-19 cases in Tokyo was reported to be 5000-18000 cases per day. In total, 632 samples were examined for SARS-CoV-2 by quantitative reverse transcription polymerase chain reaction (RT-qPCR) tests, and RT-qPCR-positive samples were subjected to a plaque assay. RESULTS: The SARS-CoV-2 RNA detection rate before and after the events ranged from 0% to 2.6% versus 0%-5.0% in environmental surface samples, respectively. However, no viable viruses were isolated from all RT-qPCR-positive samples by the plaque assay. There was no significant increase in the environmental surface contamination with SARS-CoV-2 after these events. CONCLUSIONS: These findings revealed that indirect contact transmission from environmental fomite does not seem to be of great magnitude in a community setting.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/epidemiologia , RNA Viral/genética , Japão/epidemiologia , Fatores de Risco
14.
J Infect Chemother ; 29(11): 1011-1016, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37553046

RESUMO

Neisseria gonorrhoeae is one of the important pathogens of sexually transmitted infections. N. gonorrhoeae is rapidly becoming antimicrobial resistant, and there are few drugs that are effective in the initial treatment of gonorrhea. To understand the trends of antimicrobial susceptibility of N. gonorrhoeae, the Surveillance Committee of the Japanese Society of Infectious Diseases, the Japanese Society for Chemotherapy, and the Japanese Society of Clinical Microbiology conducted the third nationwide antimicrobial susceptibility surveillance of N. gonorrhoeae isolated from male urethritis. The specimens were collected from male patients with urethritis at 30 facilities from May 2016 to July 2017. From the 159 specimens collected, 87 N. gonorrhoeae strains were isolated, and 85 were tested for susceptibility to 21 antimicrobial agents. All strains were non-susceptible to penicillin G. Seven strains (8.2%) were ß-lactamase-producing strains. The rates of susceptibility to cefixime and cefpodoxime were 96.5% and 52.9%, respectively. Three strains were non-susceptible with a minimum inhibitory concentration (MIC) of 0.5 mg/L for cefixime. None of the strains were resistant to ceftriaxone or spectinomycin. The susceptibility rate for ciprofloxacin was 23.5% (20 strains), and no strains showed intermediate susceptibility. The susceptibility rate against azithromycin was 81.2%, with one strain isolated with a MIC of 8 mg/L against azithromycin. The results of this surveillance indicate that ceftriaxone and spectinomycin, which are currently recommended for gonococcal infections in Japan, appear to be effective. It will be necessary to further expand the scale of the next surveillance to understand the current status of drug-resistant N. gonorrhoeae in Japan.


Assuntos
Anti-Infecciosos , Gonorreia , Uretrite , Humanos , Masculino , Neisseria gonorrhoeae , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefixima/farmacologia , Cefixima/uso terapêutico , Ceftriaxona/uso terapêutico , Azitromicina/uso terapêutico , Espectinomicina/farmacologia , Espectinomicina/uso terapêutico , Uretrite/tratamento farmacológico , Uretrite/epidemiologia , Uretrite/microbiologia , Japão/epidemiologia , Gonorreia/tratamento farmacológico , Gonorreia/epidemiologia , Anti-Infecciosos/uso terapêutico , Testes de Sensibilidade Microbiana
15.
BMC Public Health ; 23(1): 1489, 2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-37542210

RESUMO

BACKGROUND: This study aimed to identify the current risk factors for coronavirus disease 2019 severity and examine its association with medication use. METHODS: We used data from a large United States electronic health record database to conduct an anonymized cohort study of 171,491 patients with coronavirus disease 2019. The study was conducted from January 1, 2020, to August 27, 2021. Data on age, race, sex, history of diseases, and history of medication prescriptions were analyzed using the Cox proportional hazards model analysis to calculate hazard ratios for hospitalization and severe risk. RESULTS: Factors that increased the risk of hospitalization and critical care were age ≥ 65 years, male sex, type 2 diabetes, hypertension, interstitial pneumonia, and cardiovascular disease. In particular, age ≥ 65 years significantly increased the risk of hospitalization (hazard ratio, 2.81 [95% confidence interval, 2.58-3.07]; P < 0.001) and critical care (hazard ratio, 3.45 [2.88-4.14]; P < 0.001). In contrast, patients with hyperlipidemia had a reduced risk. However, patients with hyperlipidemia who were not taking statins had a significantly increased risk of hospitalization (hazard ratio, 1.24 [1.16-1.34]; P < 0.001). Sodium-glucose cotransporter-2 inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, glucocorticoids, and statins significantly reduced the risk of hospitalization and critical care. The risk of hospitalization and critical care increased in patients of all ethnicities with type 2 diabetes. The factors that significantly increased the risk of hospitalization in all regions were older age, hypertension, chronic obstructive pulmonary disease, and cardiovascular disease. CONCLUSION: This study identified factors that increase or reduce the risk of severe coronavirus disease. The provision of appropriate drug treatment and modification of lifestyle-related risk factors may reduce coronavirus disease severity.


Assuntos
COVID-19 , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipertensão , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Masculino , Estados Unidos/epidemiologia , Idoso , COVID-19/epidemiologia , COVID-19/terapia , Estudos de Coortes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Hospitalização , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Fatores de Risco , Cuidados Críticos , Medição de Risco
16.
Chem Pharm Bull (Tokyo) ; 71(5): 374-379, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37121688

RESUMO

Screening for bioactivity related to anti-infective, anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-viral activity, led us to identify active compounds from a methanol extract of Litsea japonica (Thub.) Juss. and the hot water extract of bark of Cinnamomum sieboldii Meisn (also known as Karaki or Okinawa cinnamon). The two main components in these extracts were identified as the catechin trimers (+)-cinnamtannin B1 and pavetannin B5. Moreover, these extracts exhibited anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity. The structures of these catechin trimers were previously determined by chemical and spectroscopic methods. Pavetanin B5 has never been reported to be isolated as a pure form and has been obtained as a mixture with another component. Although other groups have reported the putative structure of pavetannin B5, preparation of the methylated derivative of pavetannin B5 in this study allowed us to obtain the pure form for the first time as the undecamethyl derivative and confirm its exact structure. Commercially available (+)-cinnamtannin B1 and aesculitannin B (C2'-epimer of cinnamtannin B1) both of which contained pavetannin B5 as a minor component, and C. sieboldii bark extract (approx. 5/2 mixture of (+)-cinnamtannin B1/pavetannin B5) were assessed for anti-SARS-CoV-2 activity. Both C. sieboldii bark extract and commercially available aesculitannin B showed viral growth inhibitory activity.


Assuntos
COVID-19 , Catequina , Cinnamomum , Staphylococcus aureus Resistente à Meticilina , Catequina/farmacologia , Casca de Planta/química , SARS-CoV-2 , Extratos Vegetais/química
17.
J Asian Nat Prod Res ; 25(7): 704-710, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36200370

RESUMO

Determining the structures of new natural products from marine species not only enriches our understanding of the diverse chemistry of these species, but can also lead to the discovery of compounds with novel and/or important biological activities. Herein, we describe the isolation of isomaneonene C (1), a new halogenated C15 acetogenin, and three known compounds, α-snyderol (2), cis-maneonene D (3), and isomaneonene B (4), from the organic extract obtained from the red alga Laurencia cf. mariannensis collected from Iheya Island, Okinawa, Japan. The structures of these secondary metabolites were elucidated spectroscopically. All compounds were inactive at 30 µg/disc against methicillin-resistant Staphylococcus aureus (MRSA) in combination treatment with a ß-lactam drug, meropenem.


Assuntos
Laurencia , Staphylococcus aureus Resistente à Meticilina , Laurencia/química , Estrutura Molecular , Acetogeninas/farmacologia , Acetogeninas/química
18.
Antimicrob Agents Chemother ; 66(4): e0230321, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35306834

RESUMO

The purpose of this study was to investigate the population pharmacokinetics of prophylactic flomoxef based on serum and liver tissue concentrations and to demonstrate a pharmacodynamic target concentration in the serum and liver tissue exceeding the MIC in order to design an effective dosing regimen. Serum samples (n = 210) and liver tissue samples (n = 29) from 43 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index target value was regarded as the probability of maintaining flomoxef serum trough and liver tissue concentrations exceeding the MIC90 values, 0.5 mg/L and 1.0 mg/L, for Escherichia coli and methicillin-susceptible Staphylococcus aureus, respectively. The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance (CLCR) was identified as a significant covariate influencing total clearance when CLCR was less than 60 mL/min. The probability of achieving concentrations in the serum and liver tissue exceeding the MIC90 for E. coli or methicillin-susceptible S. aureus for a 1 g bolus dose was above 90% at 2 h after the initial dose. Our findings suggest that population pharmacokinetic parameters are helpful for evaluating flomoxef pharmacokinetics and determining intraoperative flomoxef redosing intervals.


Assuntos
Escherichia coli , Staphylococcus aureus , Antibacterianos/uso terapêutico , Cefalosporinas , Humanos , Fígado/cirurgia , Meticilina , Testes de Sensibilidade Microbiana
19.
J Nat Prod ; 85(11): 2641-2649, 2022 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-36282784

RESUMO

Two new antiplasmodial peptides, named koshidacins A (1) and B (2), were discovered from the culture broth of the Okinawan fungus Pochonia boninensis FKR-0564. Their structures, including absolute configurations, were elucidated by a combination of spectroscopic methods and chemical derivatization. Both compounds showed moderate in vitro antiplasmodial activity against Plasmodium falciparum strains, with IC50 values ranging from 17.1 to 0.83 µM. In addition, compound 2 suppressed 41% of malaria parasites in vivo when administered intraperitoneally at a dose of 30 mg/kg/day for 4 days.


Assuntos
Antimaláricos , Hypocreales , Peptídeos Cíclicos , Plasmodium falciparum , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Hypocreales/química , Plasmodium falciparum/efeitos dos fármacos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/farmacologia
20.
J Infect Chemother ; 28(2): 170-175, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34863648

RESUMO

INTRODUCTION: Multidrug resistant microorganisms are a serious threat to human health. Under the circumstances, a front line of antimicrobials in clinical setting may be carbapenem ß-lactams (CRBP). However, emergence of CRBP resistant (CRBP-r) Gram-negative bacteria are the most alarming. CRBP-r is mainly caused to the production of ß-lactamase, down and up expression of the diffusion channel and the efflux pump genes, respectively. Among them, production of metallo-ß-lactamase (MBL) is a major cause of high-level of CRBP-r. METHOD: We analyzed the MBL subtypes by PCR and DNA sequencing in CRBP-r Psudomonas aeruginosa in the collection of the joint program by the Japanese Association for Infectious Diseases, Japan Society for Clinical Microbiology and Japanese Society of Chemotherapy (2006-2015 in Japan). RESULTS: Among 275 strains out of a total 1716 isolates, 23 (8.3%) were MBL-positive exhibiting resistant to meropenem (MEPM), imipenem, ceftazidime, cefepime, ciprofloxacin and levofloxacin without exception and the MIC of MEPM appeared over 128 µg/mL. Their MBL subtype analysis revealed that 16, 2, and 2 isolates were IMP-1, IMP-7 and VIM-2 positive, respectively, and one isolate each expressed either IMP-10, IMP-34 or IMP-41. CONCLUSIONS: This study revealed that all the MBL-positive CRBP-r isolates were highly resistant to carbapenems dominating IMP-1 production.


Assuntos
Infecções por Pseudomonas , Pseudomonas aeruginosa , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacologia , Humanos , Japão , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/genética , beta-Lactamases/genética
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