Abstract:
:New classes of antiparasitic drugs active against Trypanosoma brucei are needed to combat human African trypanosomiasis. Inhibitors of methionyl-tRNA synthetase (MetRS) have excellent potential to be developed for this purpose (S. Shibata, J. R. Gillespie, A. M. Kelley, A. J. Napuli, Z. Zhang, K. V. Kovzun, R. M. Pefley, J. Lam, F. H. Zucker, W. C. Van Voorhis, E. A. Merritt, W. G. Hol, C. L. Verlinde, E. Fan, and F. S. Buckner, Antimicrob. Agents Chemother. 55:1982-1989, 2011). In order to assess the potential for resistance to develop against this new class of inhibitors, T. brucei cultures were grown in the presence of MetRS inhibitors or comparison drugs. Resistance up to ∼50 times the baseline 50% inhibitory concentration (IC50) was induced against a MetRS inhibitor after ∼120 days. A similar level of resistance to the clinical drug eflornithine was induced after ∼50 days and for pentamidine after ∼80 days. Thus, resistance was induced more slowly against MetRS inhibitors than against clinically used drugs. The parasites resistant to the MetRS inhibitor were shown to overexpress MetRS mRNA by a factor of 35 over the parental strain. Southern analysis indicated that the MetRS gene was amplified in the genome by nearly 8-fold. When injected into mice, the MetRS inhibitor-resistant parasites caused a reduced level of infection, indicating that the changes associated with resistance attenuated their virulence. This finding and the fact that resistance to MetRS inhibitors developed relatively slowly are encouraging for further development of this class of compounds. Published studies on other antitrypanosomal drugs have primarily shown that alterations in membrane transporters were the mechanisms responsible for resistance. This is the first published report of induced drug resistance in the African trypanosome due to overexpression of the target enzyme.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Ranade RM,Gillespie JR,Shibata S,Verlinde CL,Fan E,Hol WG,Buckner FSdoi
10.1128/AAC.02578-12subject
Has Abstractpub_date
2013-07-01 00:00:00pages
3021-8issue
7eissn
0066-4804issn
1098-6596pii
AAC.02578-12journal_volume
57pub_type
杂志文章abstract::Targeting dormant Mycobacterium tuberculosis represents a challenge to antituberculosis drug discovery programs. We previously reported and validated the use of the streptomycin (STR)-dependent M. tuberculosis 18b strain as a tool for assessing drug potency against nonreplicating bacteria both in vitro and in vivo. In...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00528-15
更新日期:2015-07-01 00:00:00
abstract::Adult AIDS Clinical Trials Group 5043 examined pharmacokinetic (PK) interactions between amprenavir (APV) and efavirenz (EFV) both by themselves and when nelfinavir (NFV), indinavir (IDV), ritonavir (RTV), or saquinavir (SQV) is added. A PK study was conducted after the administration of single doses of APV (day 0). S...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/AAC.49.8.3373-3381.2005
更新日期:2005-08-01 00:00:00
abstract::The in vitro activities of CG400549, a novel FabI inhibitor, were compared to those of linezolid and commonly used antimicrobials against recent bacterial isolates. CG400549 had an MIC(90) of 0.5 microg/ml for Staphylococcus aureus strains and was more potent than either linezolid or vancomycin. ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01562-06
更新日期:2007-07-01 00:00:00
abstract::Nucleoside reverse transcriptase inhibitors (NRTIs) used against the human immunodeficiency virus (HIV) need to be activated intracellularly to their triphosphate moiety to inhibit HIV replication. Intracellular concentrations of these NRTI triphosphates, especially zidovudine triphosphate (ZDV-TP), are relatively low...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/AAC.43.12.2964
更新日期:1999-12-01 00:00:00
abstract::Sterol delta22-desaturase has been purified from a strain of Candida glabrata with a disruption in the gene encoding sterol 14alpha-demethylase (cytochrome P-45051; CYP51). The purified cytochrome P-450 exhibited sterol delta22-desaturase activity in a reconstituted system with NADPH-cytochrome P-450 reductase in dila...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.7.1725
更新日期:1999-07-01 00:00:00
abstract::Surveillance of the circulating Mycobacterium tuberculosis complex (MTC) strains in a given locality is important for understanding tuberculosis (TB) epidemiology. We performed molecular epidemiological studies on sputum smear-positive isolates that were collected for anti-TB drug resistance surveillance to establish ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02338-13
更新日期:2014-07-01 00:00:00
abstract::We previously demonstrated the efficacy of ceftriaxone (CRO), at 50 mg/kg of body weight every 12 h, against a highly penicillin-resistant (MIC, 4 micrograms/ml) Streptococcus pneumoniae strain with low-level resistance to CRO (MIC, 0.5 microgram/ml) in a leukopenic-mouse pneumonia model (P. Moine, E. Vallée, E. Azoul...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.12.2829
更新日期:1996-12-01 00:00:00
abstract::Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, young children, elderly persons, and severely immunocompromised patients. Effective postinfection treatments are not widely available, and currently there is no approved vaccine. TMC353121 is a potent RSV fusion ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00643-10
更新日期:2010-11-01 00:00:00
abstract::We analyzed the relationship between rifampin MICs and rpoB mutations of 40 clinical isolates of Mycobacterium tuberculosis. A point mutation in either codon 516, 526, or 531 was found in 13 strains requiring MICs of > or = 64 micrograms/ml, while 21 strains requiring MICs of < or = 1 microgram/ml showed no alteration...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.4.1053
更新日期:1996-04-01 00:00:00
abstract::R plasmids identified in Pseudomonas aeruginosa strains isolated in our laboratories were classified by their incompatibility characters by using intraspecies conjugation in P. aeruginosa. The fertility factor, FP2, was compatible with R plasmids belonging to all groups, and was classified in a new group. From these d...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.10.4.573
更新日期:1976-10-01 00:00:00
abstract::The effect of tryptophan-N-formylated gramicidin (NFG) on the growth of Plasmodium berghei in mice was tested in three different experiments. NFG was shown to be capable of inhibiting the growth of the parasite in a dose-dependent way, although its action did not result in elimination of the parasite and was only temp...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.41.8.1778
更新日期:1997-08-01 00:00:00
abstract::The aim of this study was to reveal population pharmacokinetics and assess the efficacies of various dosage regimens of sulbactam in terms of the probability of target attainment with this agent over a range of MICs. Monte Carlo simulations were performed to determine the probability of attaining specific pharmacodyna...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00342-13
更新日期:2013-07-01 00:00:00
abstract::The small-colony-variant (SCV) phenotype of Staphylococcus aureus has been associated with difficult-to-treat infections, reduced antimicrobial susceptibility, and intracellular persistence. This study represents a detailed intra- and extracellular investigation of a clinical wild-type (WT) S. aureus strain and its co...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00205-10
更新日期:2011-04-01 00:00:00
abstract::A rapid microbiological assay for chlorhydroxyquinoline is described. It is a turbidimetric procedure that uses Streptococcus faecalis as the test organism. Results are available within 5 h. Data are presented to show the advantages of using a cryogenically stored inoculum over an inoculum prepared on a daily basis. ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.11.5.848
更新日期:1977-05-01 00:00:00
abstract::The in vitro activities of four fluoroquinolone compounds were tested against 92 Escherichia coli strains of ovine and caprine origin under aerobic and anaerobic incubation conditions. The four fluoroquinolones proved to be highly effective against the E. coli isolates tested. When bacteria were cultured anaerobically...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.38.10.2469
更新日期:1994-10-01 00:00:00
abstract::Pharmaceutical differences between the reference listed drug (RLD) and generic formulations of piperacillin-tazobactam may impact the reconstitution process for intravenous administration. This study evaluated the RLD against three generic formulations and measured their reconstitution times using a standardized proce...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.04563-14
更新日期:2015-03-01 00:00:00
abstract::The molecular mechanisms of resistance to fluoroquinolones, tetracyclines, an aminocyclitol, macrolides, a lincosamide, a phenicol, and pleuromutilins were investigated in Mycoplasma bovis For the identification of mutations responsible for the high MICs of certain antibiotics, whole-genome sequencing of 35 M. bovis f...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01983-16
更新日期:2017-01-24 00:00:00
abstract::Antagonism, determined by isobolograms constructed from data from combinations of ampicillin and chloramphenicol at or below the minimal inhibitory or bactericidal concentrations, was observed against 13 clinical isolates of meningococcus and against one isolate of pneumococcus. Synergy occurred against six strains of...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.15.2.240
更新日期:1979-02-01 00:00:00
abstract::Penetration of linezolid into bone and joint tissues was studied by high-performance liquid chromatography in 13 patients suffering from implant-associated infections with methicillin-resistant staphylococci. Mean concentrations of linezolid in infected tissues were greater than 10 mg/liter in a sampling time range of...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/aac.47.12.3964-3966.2003
更新日期:2003-12-01 00:00:00
abstract::Plaque formation and dye uptake assays were used to measure the MICs of PD 127,391 and PD 131,628 against Rickettsia species. The MICs of PD 127,391 were 0.25 microgram/ml for Rickettsia rickettsii and 0.125 to 0.25 microgram/ml for Rickettsia conorii. The MICs of PD 131,628 were 0.25 to 0.5 microgram/ml for R. ricket...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.11.2529
更新日期:1992-11-01 00:00:00
abstract::Acinetobacter baumannii is responsible for severe nosocomial pneumonia. To evaluate new therapeutic regimens for infections due to multiresistant strains and to study the pharmacodynamic properties of various antibiotics, we developed an experimental mouse model of acute A. baumannii pneumonia. C3H/HeN mice rendered t...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.41.2.345
更新日期:1997-02-01 00:00:00
abstract::The emergence of clinical enterococcal isolates resistant to both ampicillin and vancomycin is a cause of great concern, as there are few therapeutic alternatives for treatment of infections caused by such organisms. We evaluated the effects of the combination of ampicillin with vancomycin against vancomycin-resistant...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.10.2201
更新日期:1992-10-01 00:00:00
abstract::The in vitro susceptibility of 406 clinical isolates to BMY-28142, a new semisynthetic cephem, was evaluated and compared with cefpimizole, HR 810, ceftazidime, cefotaxime, moxalactam, and cefoperazone in a broth microdilution assay. On a weight basis, the activity of BMY-28142 against Escherichia coli, Proteus specie...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.27.4.515
更新日期:1985-04-01 00:00:00
abstract::The pharmacokinetics and bacteriological effect of ceftazidime were evaluated in rabbits experimentally infected with Streptococcus pneumoniae, Haemophilus influenzae type b, and Escherichia coli K1. The mean penetration of ceftazidime into cerebrospinal fluid after single-dose or constant-infusion administration rang...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.23.2.213
更新日期:1983-02-01 00:00:00
abstract::Microdialysis was applied to sample the unbound drug concentration in the extracellular fluid in brain and muscle of rats given zalcitabine (2',3'-dideoxycytidine; n = 4) or BEA005 (2', 3'-dideoxy-3'-hydroxymethylcytidine; n = 4) (50 mg/kg of body weight given subcutaneously). Zalcitabine and BEA005 were analyzed by h...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.42.9.2174
更新日期:1998-09-01 00:00:00
abstract::To compare the effects of four antimicrobial peptides (MUC7 12-mer, histatin 12-mer, cathelicidin KR20, and a peptide containing lactoferricin amino acids 1 to 11) on the yeast Saccharomyces cerevisiae, we employed a genomewide fitness screen of combined collections of mutants with homozygous deletions of nonessential...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01439-12
更新日期:2013-02-01 00:00:00
abstract::The activity of cefotaxime, either alone or combined with an aminoglycoside, was determined against 50 isolates of Pseudomonas aeruginosa, of which 50, 33, and 10 were resistant to gentamicin, tobramycin, and amikacin, respectively. Cefotaxime inhibited 34 isolates at a concentration of 16 microgram/ml and all isolate...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.17.3.474
更新日期:1980-03-01 00:00:00
abstract::Osteoarticular mucormycosis cases are quite rare and challenging infections that are mostly due to direct inoculation during traumatic injury among immunocompetent patients. Classic management includes a combination of aggressive surgical debridement, which may lead to amputation, and long-term systemic liposomal amph...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01006-18
更新日期:2018-12-21 00:00:00
abstract::The nonnucleoside reverse transcriptase inhibitor UC781 is under development as a potential microbicide to prevent sexual transmission of human immunodeficiency virus type 1 (HIV-1). Two gel formulations of UC781 (0.1% and 1.0%) were evaluated in a range of preclinical safety assessments, including systemic absorption...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00984-06
更新日期:2007-05-01 00:00:00
abstract::Quinazolinediones (diones) are fluoroquinolone-like inhibitors of bacterial gyrase and DNA topoisomerase IV. To assess activity against mycobacteria, C-8-methoxy dione derivatives were compared with cognate fluoroquinolones by using cultured Mycobacterium smegmatis. Diones exhibited higher MIC values than fluoroquinol...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00033-11
更新日期:2011-05-01 00:00:00