RESUMO
Opportunistic fungal infections, particularly caused by Candida albicans, remain a common cause of high morbidity and mortality in immunocompromised patients. The escalating prevalence of antifungal drug resistance necessitates the immediate exploration of alternative treatment strategies to combat these life-threatening fungal diseases. In this study, we investigated the antifungal efficacy of firsocostat, a human acetyl-CoA carboxylase (ACC) inhibitor, against C. albicans. Firsocostat alone displayed moderate antifungal activity, while combining it with voriconazole, itraconazole, or amphotericin B exhibited synergistic effects across almost all drug-sensitive and drug-resistant C. albicans strains tested. These observed synergies were further validated in two mouse models of oropharyngeal and systemic candidiasis, where the combination therapies demonstrated superior fungicidal effects compared to monotherapy. Moreover, firsocostat was shown to directly bind to C. albicans ACC and inhibit its enzymatic activity. Sequencing spontaneous firsocostat-resistant mutants revealed mutations mapping to C. albicans ACC, confirming that firsocostat has retained its target in C. albicans. Overall, our findings suggest that repurposing firsocostat, either alone or in combination with other antifungal agents, holds promising potential in the development of antifungal drugs and the treatment of candidiasis.
Assuntos
Antifúngicos , Candidíase , Animais , Camundongos , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Acetil-CoA Carboxilase , Reposicionamento de Medicamentos , Testes de Sensibilidade Microbiana , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Candida albicans , Farmacorresistência Fúngica , Fluconazol/farmacologiaRESUMO
Currently, Helicobacter pylori eradication by antibiotic therapy faces various challenges, including antibiotic resistance, side effects on intestinal commensal bacteria, and patient compliance. In this study, loureirin A (LrA), a traditional Chinese medicine monomer extracted from Sanguis Draconis flavones, was found to possess specific antibacterial activity against H. pylori without the bacteria displaying a tendency to develop resistance in vitro. LrA demonstrated a synergistic or additive effect when combined with omeprazole (a proton pump inhibitor) against H. pylori. The combination of LrA and omeprazole showed promising anti-H. pylori potential, exhibiting notable in vivo efficacy comparable to standard triple therapy in mouse models infected with both drug-sensitive and drug-resistant H. pylori strains. Moreover, the narrow-spectrum antibacterial profile of LrA is reflected in its minimal effect on the diversity and composition of the mouse gut microbiota. The underlying mechanism of action of LrA against H. pylori involves the generation of bactericidal levels of reactive oxygen species, resulting in apoptosis-like cell death. These findings indicate that LrA is a promising lead compound targeting H. pylori without harming the commensal bacteria.
RESUMO
BACKGROUND: The current standard treatment for Helicobacter pylori infection, which involves a combination of two broad-spectrum antibiotics, faces significant challenges due to its detrimental impact on the gut microbiota and the emergence of drug-resistant strains. This underscores the urgent requirement for the development of novel anti-H. pylori drugs. Zoliflodacin, a novel bacterial gyrase inhibitor, is currently undergoing global phase III clinical trials for treating uncomplicated Neisseria gonorrhoeae. However, there is no available data regarding its activity against H. pylori. MATERIALS AND METHODS: We evaluated the in vitro activity of zoliflodacin against H. pylori clinical isolates (n = 123) with diverse multidrug resistance. We performed DNA gyrase supercoiling and microscale thermophoresis assays to identify the target of zoliflodacin in H. pylori. We analyzed 2262 H. pylori whole genome sequences to identify Asp424Asn and Lys445Asn mutations in DNA gyrase subunit B (GyrB) that are associated with zoliflodacin resistance. RESULTS: Zoliflodacin exhibits potent activity against all tested isolates, with minimal inhibitory concentration (MIC) values ranging from 0.008 to 1 µg/mL (MIC50: 0.125 µg/mL; MIC90: 0.25 µg/mL). Importantly, there was no evidence of cross-resistance to any of the four first-line antibiotics commonly used against H. pylori. We identified GyrB as the primary target of zoliflodacin, with Asp424Asn or Lys445Asn substitutions conferring resistance. Screening of 2262 available H. pylori genomes for the two mutations revealed only one clinical isolate carrying Asp424Asn substitution. CONCLUSION: These findings support the potential of zoliflodacin as a promising candidate for H. pylori treatment, warranting further development and evaluation.
Assuntos
Barbitúricos , Infecções por Helicobacter , Helicobacter pylori , Isoxazóis , Morfolinas , Oxazolidinonas , Compostos de Espiro , Humanos , Antibacterianos/farmacologia , DNA Girase/genética , Farmacorresistência Bacteriana , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Testes de Sensibilidade Microbiana , Ensaios Clínicos Fase III como AssuntoRESUMO
Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S.aureus within host cells may cause long-term colonization and clinical failure. Current treatments have poor efficacy in clearing intracellular bacteria. Antibody-antibiotic conjugates (AACs) is a novel strategy for eliminating intracellular bacteria. Herein, we use KRM-1657 as payload of AAC for the first time, and we conjugate it with anti S. aureus antibody via a dipeptide linker (Valine-Alanine) to obtain a novel AAC (ASAK-22). The ASAK-22 exhibits good in vitro pharmacokinetic properties and inhibitory activity against intracellular MRSA, with 100 µg/mL of ASAK-22 capable of eliminating intracellular MRSA to the detection limit. Furthermore, the in vivo results demonstrate that a single administration of ASAK-22 significantly reduces the bacterial burden in the bacteremia model, which is superior to the vancomycin treatment.
Assuntos
Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Animais , Humanos , Camundongos , Antibacterianos/farmacologia , Antibacterianos/química , Relação Dose-Resposta a Droga , Imunoconjugados/química , Imunoconjugados/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Infecções Estafilocócicas/tratamento farmacológico , Relação Estrutura-Atividade , Rifamicinas/química , Rifamicinas/farmacologiaRESUMO
Six new citrinin derivatives (1, 2, 4, 10, 11, and 16), along with fourteen known analogues, were acquired from Penicillium sp. TW131-64, a marine-derived fungus strain. The chemical structures of new compounds were identified through adopting various spectroscopic methods in combination with X-ray diffraction technology and comparison of the experimental electronic circular dichroism (ECD) with calculated ones. Among them, compounds 1-4 were nitrogen-containing citrinin derivatives existing in enantiomers which were resolved by chiral chromatography. A putative biosynthetic pathway for compounds 1-4 was proposed. Additionally, the antimicrobial activities of these compounds were detected by the broth microdilution assays. Citrinin derivatives 1, 2, 4 and their corresponding enantiomers (1a, 2a, 4a, 1b, 2b, and 4b) exhibited potent antimicrobial activities towards Helicobacter pylori standard strains and multidrug-resistant strains (MIC values ranging from 0.25 to 8 µg/mL), which were comparable or even better than metronidazole. Moreover, compounds 1a and 1b also showed remarkable broad antimicrobial effects towards Staphylococcus aureus, Enterococcus faecalis, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, vancomycin-resistant Enterococcus faecium (VRE), and Candida albicans. In summary, our studies demonstrated that citrinin enantiomers 1a-4a and 1b-4b, especially 1a and 1b, can be lead compounds in the research and development (R & D) of novel antimicrobial drugs. KEY POINTS: ⢠3 novel nitrogen-containing citrinin derivatives (1, 2, 4) were isolated. ⢠citrinin derivatives 1-4 in enantiomers were resolved by chiral chromatography. ⢠citrinin derivatives 1a and 1b showed broad and significant antimicrobial effects.
Assuntos
Anti-Infecciosos , Citrinina , Staphylococcus aureus Resistente à Meticilina , Penicillium , Citrinina/farmacologia , Antibacterianos/química , Fungos , Anti-Infecciosos/farmacologia , Nitrogênio/farmacologia , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Alternarialone A (1), one new curvularin derivative, and two known compounds (2 and 3) were isolated from the crude extract of the mangrove-derived fungus Alternaria longipes. Their structures were elucidated by comprehensive spectroscopic analyses, including MS and NMR spectroscopic data. The absolute configuration of 1 was assigned by 13C NMR calculations and a comparison of electronic circular dichroism (ECD) spectra. All compounds were evaluated for their antibacterial activities against Helicobacter pylori. Compounds 2 and 3 showed antibacterial activities against H. pylori G27 with MIC values of 8 and 16 µg/ml, respectively, while compound 3 also displayed antibacterial activity against H. pylori BHKS159 with the MIC value of 16 µg/ml.
Assuntos
Alternaria , Zearalenona , Alternaria/química , Antibacterianos/química , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Seven new naphthoquinone diglycosides (1-7), three new anthraquinones (8-10), and eight known analogues were obtained from the aerial parts of Mitracarpus hirtus collected from West Africa in a bioassay-guided phytochemical investigation. All isolated compounds were elucidated by comparison with the literature and interpretation of spectroscopic data, and the absolute configurations of the new naphthoquinone diglycosides (1-10) were confirmed by chemical methods and ECD calculations. Notably, compound 1 was found to be the first naphthoquinone diglycoside containing carboxylic acid and isopentenyl side chains isolated from a species in the genus Mitracarpus. Compounds 6-18 showed antibacterial activity against multiple Helicobacter pylori strains with MIC values ranging from 0.0625 to 64 µg/mL. Particularly, 1-hydroxybenzoisochromanquinone (17) and benzo[g]isoquinoline-5,10-dione (18), with MIC values of 0.0625 and 0.125 µg/mL, displayed 32-512-fold higher potencies than a positive control, metronidazole. Compound 18 also demonstrated high antibiofilm activity and killed biofilm-encased Helicobacter pylori cells more effectively than metronidazole.
Assuntos
Helicobacter pylori , Naftoquinonas , Rubiaceae , Antibacterianos/farmacologia , Benzoquinonas , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , Naftoquinonas/farmacologia , Componentes Aéreos da PlantaRESUMO
As a member of the potassium calcium-activated channel subfamily, increasing evidence suggests that KCNN4 was associated with malignancies. However, the roles and regulatory mechanisms of KCNN4 in PDAC have been little explored. In this work, we demonstrated that the level of KCNN4 in PDAC was abnormally elevated, and the overexpression of KCNN4 was induced by transcription factor AP-1. KCNN4 was closely correlated with unfavorable clinicopathologic characteristics and poor survival. Functionally, we found that overexpression of KCNN4 promoted PDAC cell proliferation, migration and invasion. Conversely, the knockdown of KCNN4 attenuated the growth and motility of PDAC cells. In addition to these, knockdown of KCNN4 promoted PDAC cell apoptosis and led to cell cycle arrest in the S phase. In mechanistic investigations, RNA-sequence revealed that the MET-mediated AKT axis was essential for KCNN4, encouraging PDAC cell proliferation and migration. Collectively, these findings reveal a function of KCNN4 in PDAC and suggest it's an attractive therapeutic target and tumor marker. Our studies underscore a better understanding of the biological mechanism of KCNN4 in PDAC and suggest novel strategies for cancer therapy.
Assuntos
Carcinoma Ductal Pancreático/patologia , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Apoptose/fisiologia , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Fator de Transcrição AP-1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias PancreáticasRESUMO
Marine fungi-derived secondary metabolites are still an important source for the discovery of potential antimicrobial agents. Here, five new polyketides (1, 2, and 6-8) and seven known compounds (3-5 and 9-12) were obtained from the culture of the marine-derived fungus Trichoderma sp. JWM29-10-1. Their structures were identified by extensive spectrographic data analyses, including 1D and 2D NMR, UV, IR, and HR-ESI-MS. Further, the absolute configurations of new compounds were determined by circular dichroism (CD) spectrum and alkali-hydrolysis in combination with the in situ dimolybdenum CD method. Subsequently, the antimicrobial effects of these isolated compounds were assessed by examining the minimal inhibition concentration (MIC) with the broth microdilution assay. Compounds 1 and 2 exhibited potent antimicrobial activity against Helicobacter pylori, including multidrug-resistant strains, with MIC range values of 2-8 µg/mL. Moreover, compound 1 showed significant inhibitory effects on the growth of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, and vancomycin-resistant Enterococcus faecium, which greatly threaten human health. This study demonstrates that chromone derivatives 1-2, especially for 1, could be potential lead compounds for the development of new antimicrobial agents and provides insight for future medicinal chemistry research.
Assuntos
Anti-Infecciosos , Fontes Hidrotermais , Staphylococcus aureus Resistente à Meticilina , Policetídeos , Trichoderma , Humanos , Policetídeos/farmacologia , Policetídeos/química , Anti-Infecciosos/químicaRESUMO
Two new austocystin analogs, austocystin P (1) and austocystin Q (2), along with fourteen known compounds (3-16) were isolated from the fermentation extract of Aspergillus sp. WHUF05236. The planar structures of 1 and 2 were elucidated through 1D, 2D NMR and MS analyses. Their absolute configurations were determined by the time-dependent density functional (TDDFT)-ECD calculation. Compounds 3, 11, and 12 exhibited antimicrobial activities against Helicobacter pylori with MIC values ranging from 20.00 to 43.47â µM. Compounds 3, 6, and 7 showed cytotoxicities against the human colon cancer cell lines Hct-116 with IC50 values of 101.79, 65.46, and 36.72â µM, respectively.
Assuntos
Aspergillus , Fungos , Aspergillus/química , Fungos/química , Humanos , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Helicobacter pylori is a major global pathogen and has been implicated in gastritis, peptic ulcer, and gastric carcinoma. The efficacy of the extensive therapy of H. pylori infection with antibiotics is compromised by the development of drug resistance and toxicity toward human gut microbiota, which urgently demands novel and selective antibacterial strategies. The present study was mainly performed to assess the in vitro and in vivo effects of a natural herbal compound, dihydrotanshinone I (DHT), against standard and clinical H. pylori strains. DHT demonstrated effective antibacterial activity against H. pyloriin vitro (MIC50/90, 0.25/0.5 µg/ml), with no development of resistance during continuous serial passaging. Time-kill curves showed strong time-dependent bactericidal activity for DHT. Also, DHT eliminated preformed biofilms and killed biofilm-encased H. pylori cells more efficiently than the conventional antibiotic metronidazole. In mouse models of multidrug-resistant H. pylori infection, dual therapy with DHT and omeprazole showed in vivo killing efficacy superior to that of the standard triple-therapy approach. Moreover, DHT treatment induces negligible toxicity against normal tissues and exhibits a relatively good safety index. These results suggest that DHT could be suitable for use as an anti-H. pylori agent in combination with a proton pump inhibitor to eradicate multidrug-resistant H. pylori.
Assuntos
Antiulcerosos , Infecções por Helicobacter , Helicobacter pylori , Preparações Farmacêuticas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Quimioterapia Combinada , Infecções por Helicobacter/tratamento farmacológico , Humanos , Metronidazol/farmacologia , Metronidazol/uso terapêutico , OmeprazolRESUMO
Acidovorax citrulli is a seedborne pathogen that causes bacterial fruit blotch (BFB), a global threat to watermelon production. Treating watermelon seeds to eliminate A. citrulli is a critical component of BFB management, and several strategies have been evaluated to mitigate the impact of the disease. In China, watermelon seed producers routinely incubate seeds in watermelon juice (fermentation) to reduce the risk of seed infection by A. citrulli and seedling transmission of BFB. However, there has been limited effort to evaluate the efficacy of fermentation in mitigating A. citrulli seed infection. The current study showed that fermented watermelon fruit juice could inhibit A. citrulli population growth and demonstrated that the low pH conditions, not the temperature dynamic, generated during fermentation might play a major role in A. citrulli growth inhibition and could induce the viable but nonculturable (VBNC) state in A. citrulli. We developed an effective method that was based on propidium monoazide PCR to detect viable A. citrulli cells under low pH conditions or in fermented watermelon fruit juice. We also provided evidence that VBNC A. citrulli cells induced by fermented watermelon fruit juice could not be resuscitated and did not retain their virulence on watermelon seedlings. However, VBNC A. citrulli cells could be resuscitated in Luria-Bertani medium. Based on these observations, we conclude that fermentation in watermelon fruit juice may not be an effective seed treatment for BFB because it may increase the seed infection by A. citrulli.
Assuntos
Citrullus , China , Comamonadaceae , Fermentação , Frutas , Doenças das Plantas , SementesRESUMO
Marine fungi are well known for their ability to produce a multitude of natural products and have been proved to be a particularly rich source of drug leads. Here, 20 pyrones and their analogs (1-20), including two new compounds (1 and 6), were obtained from a marine-derived fungus strain of Aspergillus sp. DM94. Their structures were determined by analyses of UV, IR, HR-ESI-MS, and NMR data. The ability to inhibit Helicobacter pylori in vitro was assessed for these isolated compounds. Results showed that the bis-naphtho-γ-pyrones exhibited potent antibacterial activity against both the standard and multidrug-resistant H. pylori strains. Structure-activity relationship (SAR) analysis suggested that the bis-naphtho[2,3-b]pyrones showed better anti-H. pylori activity than a hybrid of naphtho[2,3-b]pyrone and naphtho[1,2-b]pyrone. In addition, the free hydroxyl group of the C-8 position in the lower unit is vital for its anti-H. pylori activity. Importantly, compound 18 showed a synergistic effect in combination with amoxicillin, clarithromycin, or metronidazole, suggesting its potential use to overcome antibiotic resistance of H. pylori. This study shed light on the discovery of new anti-H. pylori agents. KEY POINTS: ⢠New pyrones discovered from a marine-derived fungus Aspergillus sp. DM94. ⢠Bis-naphtho-γ-pyrones showed potent anti-H. pylori activity. ⢠The anti-H. pylori SAR analysis of bis-naphtho-γ-pyrones was discussed. ⢠Bis-naphtho-γ-pyrone 18 showed synergistic effect with clinical antibiotics.
Assuntos
Anti-Infecciosos , Helicobacter pylori , Antibacterianos/farmacologia , Aspergillus , Testes de Sensibilidade Microbiana , Pironas/farmacologiaRESUMO
Cyclopropane fatty acids (CFAs) are synthetized by the addition of a methylene group from S-adenosyl-l-methionine across the carbon-carbon double bonds of unsaturated fatty acid chains of membrane phospholipids. This fatty acid cyclopropanation, catalyzed by the CFA synthase (CfaS) enzyme, occurs in many bacteria, including the human pathogen Helicobacter pylori Although the cyclopropane modification was reported to play a key role in the adaptation in response to environmental stress, its role in H. pylori remains unknown. In this study, we showed that H. pylori HP0416 encodes a functional CfaS. The enzyme was demonstrated to be required for acid resistance, antibiotic resistance, intracellular survival and mouse gastric colonization, and cell membrane integrity. Moreover, the tool compound dioctylamine, which acts as a substrate mimic, directly inhibits the CfaS function of H. pylori, resulting into sensitivity to acid stress, increased antibiotic susceptibility, and attenuated abilities to avoid macrophage killing and to colonize mouse stomachs. These results validate CfaS as a promising antibiotic target and provide new potentials for this recognized target in future anti-H. pylori drug discovery efforts.IMPORTANCE The increasing prevalence of multidrug-resistant Helicobacter pylori strains has created an urgent need for alternative therapeutic regimens that complement the current antibiotic treatment strategies for H. pylori eradication; however, this is greatly hampered due to a lack of "druggable" targets. Although the CFAs are present in H. pylori cytoplasmic membranes at high levels, their physiological role has not been established. In this report, deletion of the CFA synthase CfaS was shown to attenuate acid and drug resistance, immune escape, and gastric colonization of H. pylori These findings were validated by inhibition of the CfaS activity with the tool compound dioctylamine. These studies identify this enzyme as an attractive target for further drug discovery efforts against H. pylori.
Assuntos
Resistência Microbiana a Medicamentos , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Metiltransferases/metabolismo , Aminas/farmacologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Ciclopropanos/metabolismo , Ácidos Graxos/metabolismo , Feminino , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/enzimologia , Helicobacter pylori/genética , Humanos , Metiltransferases/antagonistas & inibidores , Metiltransferases/genética , Camundongos , Fatores de Virulência/genética , Fatores de Virulência/metabolismoRESUMO
Helicobacter pylori is a major global pathogen, and its infection represents a key factor in the etiology of various gastric diseases, including gastritis, peptic ulcers, and gastric carcinoma. The efficacy of current standard treatment for H. pylori infection including two broad-spectrum antibiotics is compromised by toxicity toward the gut microbiota and the development of drug resistance, which will likely only be resolved through novel and selective antibacterial strategies. Here, we synthesized a small molecule, zinc linolenate (ZnLla), and investigated its therapeutic potential for the treatment of H. pylori infection. ZnLla showed effective antibacterial activity against standard strains and drug-resistant clinical isolates of H. pyloriin vitro with no development of resistance during continuous serial passaging. The mechanisms of ZnLla action against H. pylori involved the disruption of bacterial cell membranes and generation of reactive oxygen species. In mouse models of multidrug-resistant H. pylori infection, ZnLla showed in vivo killing efficacy comparable and superior to the triple therapy approach when use as a monotherapy and a combined therapy with omeprazole, respectively. Moreover, ZnLla treatment induces negligible toxicity against normal tissues and causes minimal effects on both the diversity and composition of the murine gut microbiota. Thus, the high degree of selectivity of ZnLla for H. pylori provides an attractive candidate for novel targeted anti-H. pylori treatment.
Assuntos
Antibacterianos/farmacologia , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Gastropatias/tratamento farmacológico , Ácido alfa-Linolênico/farmacologia , Animais , Farmacorresistência Bacteriana , Feminino , Infecções por Helicobacter/microbiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Omeprazol/farmacologia , Especificidade da Espécie , Gastropatias/microbiologiaRESUMO
Armeniaspirols (1-3) are potent antibiotics against Gram-positive pathogens. Through a biosynthetic investigation, we identified four enzymes involved in the structural modification of 1-3. Manipulation of their activity led to the generation of 4-6 and nine novel analogues, 7-15. Bioactivity assessments revealed that the pyrrole chloro group and the methyl group are important for the antimicrobial activities of armeniaspirols, which lays the foundation for future structure optimization and mechanism of action studies of armeniaspirols.
Assuntos
Antibacterianos/biossíntese , Família Multigênica , Pirróis/metabolismo , Compostos de Espiro/metabolismo , Streptomyces/genética , Pirróis/farmacologia , Compostos de Espiro/farmacologiaRESUMO
The biosynthesis of the pimelate moiety of biotin in Escherichia coli requires two specialized proteins, BioC and BioH. However, the enzymes that have BioC- or BioH-like activities show remarkable sequence diversity among biotin-producing bacteria. Here, we report that the intracellular rickettsial pathogen Ehrlichia chaffeensis encodes two novel proteins, BioT and BioU, which functionally replace the E. coli BioC and BioH proteins, respectively. The desthiobiotin assays demonstrated that these two proteins make pimeloyl-acyl carrier protein (ACP) from the substrate malonyl-ACP with the aid of the FAS II pathway, through the expected pimeloyl-ACP methyl ester intermediate. BioT and BioU homologues seem restricted to the species of Ehrlichia and its close relative, Anaplasma. Taken together, the synthesis of the biotin precursor in E. chaffeensis appears to be catalyzed by two novel BioC- and BioH-like proteins.
Assuntos
Proteínas de Bactérias/genética , Biotina/biossíntese , Ehrlichia chaffeensis/genética , Proteínas de Escherichia coli/genética , Proteína de Transporte de Acila/genética , Proteína de Transporte de Acila/metabolismo , Proteínas de Bactérias/metabolismo , Vias Biossintéticas , Catálise , Escherichia coli/genética , Escherichia coli/metabolismo , Especificidade por SubstratoRESUMO
A new pyrazine derivative, trypilepyrazinol (1), a new α-pyrone polyketide, (+)-neocitreoviridin (2), and a new ergostane analogue, 3ß-hydroxyergosta-8,14,24(28)-trien-7-one (3), were isolated and characterized along with five known compounds from the marine-derived fungus Penicillium sp. IMB17-046. The structures of these new compounds were determined using spectroscopic data analyses (HRESIMS, 1D- and 2D-NMR), X-ray crystallography analysis, and TDDFT ECD calculation. Compounds 1 and 3 exhibited broad-spectrum antiviral activities against different types of viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza A virus (IAV), with IC50 values ranging from 0.5 to 7.7 µM. Compounds 1 and 2 showed antibacterial activities against Helicobacter pylori, a causative pathogen of various gastric diseases, with minimum inhibitory concentration (MIC) values of 1-16 µg/mL.