Abstract:
:Heat shock protein 90 (Hsp90) is an essential chaperone involved in the fungal stress response that can be harnessed as a novel antifungal target for the treatment of invasive aspergillosis. We previously showed that genetic repression of Hsp90 reduced Aspergillus fumigatus virulence and potentiated the effect of the echinocandin caspofungin. In this study, we sought to identify sites of posttranslational modifications (phosphorylation or acetylation) that are important for Hsp90 function in A. fumigatus. Phosphopeptide enrichment and tandem mass spectrometry revealed phosphorylation of three residues in Hsp90 (S49, S288, and T681), but their mutation did not compromise Hsp90 function. Acetylation of lysine residues of Hsp90 was recovered after treatment with deacetylase inhibitors, and acetylation-mimetic mutations (K27A and K271A) resulted in reduced virulence in a murine model of invasive aspergillosis, supporting their role in Hsp90 function. A single deletion of lysine K27 or an acetylation-mimetic mutation (K27A) resulted in increased susceptibility to voriconazole and caspofungin. This effect was attenuated following a deacetylation-mimetic mutation (K27R), suggesting that this site is crucial and should be deacetylated for proper Hsp90 function in antifungal resistance pathways. In contrast to previous reports in Candida albicans, the lysine deacetylase inhibitor trichostatin A (TSA) was active alone against A. fumigatus and potentiated the effect of caspofungin against both the wild type and an echinocandin-resistant strain. Our results indicate that the Hsp90 K27 residue is required for azole and echinocandin resistance in A. fumigatus and that deacetylase inhibition may represent an adjunctive anti-Aspergillus strategy.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Lamoth F,Juvvadi PR,Soderblom EJ,Moseley MA,Asfaw YG,Steinbach WJdoi
10.1128/AAC.02286-13subject
Has Abstractpub_date
2014-01-01 00:00:00pages
1889-96issue
4eissn
0066-4804issn
1098-6596pii
AAC.02286-13journal_volume
58pub_type
杂志文章abstract::Enfuvirtide is the first fusion and entry inhibitor approved for use for the treatment of human immunodeficiency virus (HIV) type 1 infection and as such represents a novel class of agents. For the population of patients experienced with three antiretroviral classes, enfuvirtide provides an additional option for treat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
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更新日期:2008-12-01 00:00:00
abstract::Twelve healthy volunteers participated in this randomized crossover study to compare the concentrations and recovery levels of fleroxacin and pefloxacin in urine and to assess their bactericidal activities against 12 strains of urinary pathogens with different susceptibilities over a wide range of MICs. The volunteers...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1998-07-01 00:00:00
abstract::According to recommendations of the 6th WHO Advisory Committee on Buruli ulcer, directly observed treatment with the combination of rifampin and streptomycin, administered daily for 8 weeks, was recommended to 310 patients diagnosed with Buruli ulcer in Pobè, Bénin. Among the 224 (72%) eligible patients for whom treat...
journal_title:Antimicrobial agents and chemotherapy
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更新日期:2007-11-01 00:00:00
abstract::The antibacterial drug nalidixic acid (Nal) can suppress the growth of Candida albicans at levels of the drug normally found in urine. Growth suppression increases as drug levels are increased, and Nal also causes a similar proportional inhibition of the synthesis of all cellular macromolecules. However, growth temper...
journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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abstract::We tested the combined activity of vancomycin and seven beta-lactam antibiotics against Staphylococcus aureus clinical strain Mu3, which displays heterogeneous resistance to vancomycin. When combined with vancomycin, four of the seven tested beta-lactams exhibited an additive effect at or near their MICs, while all sh...
journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/AAC.45.4.1292-1294.2001
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abstract::The incidence rates of travelers' diarrhea (TD) have remained high for the last 50 years. More recently, there have been increasing recommendations for self-initiated therapy and use of prophylactic drugs for TD. We last examined the in vitro susceptibilities of commonly used antibiotics against TD pathogens in 1997. ...
journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/AAC.00739-10
更新日期:2011-02-01 00:00:00
abstract::Malaria and trypanosomiasis are diseases which afflict millions and for which novel therapies are urgently required. We have tested two well-characterized cell-penetrating peptides (CPPs) for antiparasitic activity. One CPP, designated TP10, has broad-spectrum antiparasitic activity against Plasmodium falciparum, both...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01450-07
更新日期:2008-09-01 00:00:00
abstract::Previously, we reported potent activity of a novel spiropyrimidinetrione, zoliflodacin, against N. gonorrhoeae isolates from symptomatic men in Nanjing, China, collected in 2013. Here, we investigated trends of susceptibilities of zoliflodacin in 986 isolates collected from men between 2014 and 2018. N. gonorrhoeae is...
journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/AAC.00863-20
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00260-06
更新日期:2006-07-01 00:00:00
abstract::We previously showed that simian immunodeficiency virus-infected macaque macrophages contacting uninfected CD4+ lymphocytes caused extensive cell fusion and synthesis of phlogistic cytokines. In this study, macaque macrophage cultures inoculated with SIVmac251 and treated simultaneously with 10 microM 3'-azidothymidin...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.2.360
更新日期:1993-02-01 00:00:00
abstract::Few oral antibiotics exist for the empirical treatment of extended-spectrum β-lactamase (ESBL) urinary tract infections (UTI). In this study, we sought to determine the activity of fosfomycin against ESBL-producing uropathogens from patients at 3 Veterans Affairs (VA) facilities between 2010 and 2013. Among the ESBL u...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02614-15
更新日期:2015-11-23 00:00:00
abstract::Most surveys for class 1 integrons are at least partly predicated on PCR screening that targets integron conserved regions. However, class 1 integrons are structurally diverse, so dependence on conserved regions may lead to missing clinically relevant examples of class 1 integrons. Here, we surveyed a commensal popula...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01831-10
更新日期:2011-08-01 00:00:00
abstract::Clostridium difficile is a leading cause of health care-associated diarrhea with significant morbidity and mortality, and new options for the treatment of C. difficile-associated diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clinical development for treatment of CDAD...
journal_title:Antimicrobial agents and chemotherapy
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更新日期:2014-01-01 00:00:00
abstract::PSI-352938 is a novel cyclic phosphate prodrug of β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methylguanosine 5'-monophosphate that has potent activity against hepatitis C virus (HCV) in vitro. The studies described here characterize the in vitro anti-HCV activity of PSI-352938, alone and in combination with other inhibitors of H...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00032-11
更新日期:2011-06-01 00:00:00
abstract::One gram of ceftriaxone was given intravenously to 15 patients approximately 2 h before cardiopulmonary bypass surgery. Ceftriaxone levels in plasma (mean +/- standard deviation) were 60.4 +/- 18.8 micrograms/ml (range, 17.0 to 96.0 micrograms/ml) at the beginning of bypass, 44.2 +/- 16.6 micrograms/ml (range, 9.4 to ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.25.1.37
更新日期:1984-01-01 00:00:00
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doi:10.1128/aac.4.6.607
更新日期:1973-12-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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abstract::Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh an...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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更新日期:2017-12-21 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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更新日期:1974-04-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.48.5.1593-1599.2004
更新日期:2004-05-01 00:00:00
abstract::One way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series of Mycobacterium tuberculosis gy...
journal_title:Antimicrobial agents and chemotherapy
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更新日期:2015-04-01 00:00:00
abstract::Resistance of Mycobacterium tuberculosis to fluoroquinolones (FQ) results mostly from mutations in the gyrA gene. We developed a reverse hybridization-based line probe assay in which oligonucleotide probes carrying the wild-type gyrA sequence, a serine-to-threonine (S95T) polymorphism, and gyrA mutations (A90V, A90V-S...
journal_title:Antimicrobial agents and chemotherapy
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