Abstract:
:Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Inoyama D,Paget SD,Russo R,Kandasamy S,Kumar P,Singleton E,Occi J,Tuckman M,Zimmerman MD,Ho HP,Perryman AL,Dartois V,Connell N,Freundlich JSdoi
10.1128/AAC.02063-17subject
Has Abstractpub_date
2018-02-23 00:00:00issue
3eissn
0066-4804issn
1098-6596pii
AAC.02063-17journal_volume
62pub_type
杂志文章abstract::OXA-48-like carbapenemases have only recently emerged in Europe. OXA-162 is a rare OXA-48 variant usually coexpressed with extended-spectrum β-lactamases. Here, we report the identification of the first OXA-162 carbapenemase-producing Klebsiella pneumoniae isolates, which coexpressed an AmpC cephalosporinase (DHA-1), ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01514-15
更新日期:2015-12-14 00:00:00
abstract::3-O-(3',3'-Dimethylsuccinyl) betulinic acid (DSB), also known as PA-457, bevirimat (BVM), or MPC-4326, is a novel HIV-1 maturation inhibitor. Unlike protease inhibitors, BVM blocks the cleavage of the Gag capsid precursor (CA-SP1) to mature capsid (CA) protein, resulting in the release of immature, noninfectious viral...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01435-10
更新日期:2011-07-01 00:00:00
abstract::Antimicrobial cationic peptides are ubiquitous in nature and are thought to be a component of the first line of defense against infectious agents. It is widely believed that the killing mechanism of these peptides on bacteria involves an interaction with the cytoplasmic membrane. Cationic peptides from different struc...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.8.2086-2092.2000
更新日期:2000-08-01 00:00:00
abstract::The 18-amino-acid cationic, tryptophan-rich ApoEdpL-W peptide derived from human ApoE apolipoprotein was shown to have antifungal activity against pathogenic yeasts of the Candida genus (except C. glabrata). ApoEdpL-W was active against planktonic cells and early-stage biofilms but less active against mature biofilms,...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00319-11
更新日期:2011-10-01 00:00:00
abstract::In enterobacteria, the ampG gene encodes a transmembrane protein (permease) that transports 1,6-GlcNAc-anhydro-MurNAc and the 1,6-GlcNAc-anhydro-MurNAc peptide from the periplasm to the cytoplasm, which serve as signal molecules for the induction of ampC β-lactamase. The role of AmpG as a transporter is also essential...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00009-10
更新日期:2010-11-01 00:00:00
abstract::Streptonigrin, a quinone antitumor antibiotic, has been reported to be effective in human trials. A sensitive and precise microbiological assay for the determination of distribution and concentrations of streptonigrin in the body fluids and tissues of treated mice has been developed in an attempt to supplement success...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.5.1.82
更新日期:1974-01-01 00:00:00
abstract::Acanthamoeba keratitis is a severe ocular infection secondary to accidental macro- or microscopic trauma of the cornea. Starting in 1985, a dramatic increase of this infection was recorded along with the spread of contact lens use. This protozoal disease is difficult to treat because of the scarcity of efficacious top...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.42.9.2232
更新日期:1998-09-01 00:00:00
abstract::We have used the endogenous reverse transcriptase reaction of viral core particles from duck liver to elucidate the mechanism of inhibition of duck hepatitis B virus (DHBV) replication by the nucleoside analog (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (3TC). As is the case in human immunodeficiency virus replication, 3...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.39.7.1430
更新日期:1995-07-01 00:00:00
abstract::The efficacies of cilofungin and amphotericin B separately and together in mice with disseminated candidiasis were studied. Male CD-1 mice (age, 5 weeks) were infected intravenously with 3 X 10(5) CFU of Candida albicans. At 4 days postinfection, intraperitoneal therapy was initiated and was continued for 14 days. The...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.35.7.1334
更新日期:1991-07-01 00:00:00
abstract::Occidiofungin is produced by the soil bacterium Burkolderia contaminans MS14 and is structurally similar or identical to the burkholdines, xylocandins, and cepacidines. This study identified the primary cellular target of occidiofungin, which was determined to be actin. The modification of occidiofungin with a functio...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01585-18
更新日期:2018-12-21 00:00:00
abstract::Dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a well-validated antifolate drug target in certain pathogenic apicomplexans, but not in the genus Babesia, including Babesia gibsoni. Therefore, we isolated, cloned, and expressed the wild-type B. gibsoni dhfr-ts gene in Escherichia coli and evaluated the inhib...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00384-08
更新日期:2008-11-01 00:00:00
abstract::Linezolid is the first member of the oxazolidinones and is active against drug-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA). Additionally, linezolid shows an immunomodulatory effect, such as inhibition of inflammatory cytokine production. In this study, we examined the ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02811-13
更新日期:2014-07-01 00:00:00
abstract::This study compared nine susceptibility testing methods and 12 endpoints for anidulafungin, caspofungin, and micafungin with the same collection of blinded FKS hot spot mutant (n = 29) and wild-type isolates (n = 94). The susceptibility tests included EUCAST Edef 7.1, agar dilution, Etest, and disk diffusion with RPMI...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01256-09
更新日期:2010-01-01 00:00:00
abstract::The in vitro potency and in vivo efficacy of Q-35, a new fluoroquinolone, against Mycoplasma pneumoniae were investigated by pharmacokinetic studies with M. pneumoniae-infected hamsters. By using fluoroquinolones, macrolides, and tetracyclines as references, Q-35 was found to possess the greatest mycoplasmacidal activ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.9.1826
更新日期:1993-09-01 00:00:00
abstract::Development of anthrax countermeasures that may be used concomitantly in a postexposure setting requires an understanding of the interaction between these products. Anthrax immune globulin intravenous (AIGIV) is a candidate immunotherapeutic that contains neutralizing antibodies against protective antigen (PA), a comp...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00460-13
更新日期:2013-11-01 00:00:00
abstract::Carbapenemase-producing Enterobacteriaceae isolates (n = 110) from health care centers in central Indiana (from 2010 to 2013) were tested for susceptibility to combinations of avibactam (4 μg/ml) with ceftazidime, ceftaroline, or aztreonam. MIC50/MIC90 values were 1/2 μg/ml (ceftazidime-avibactam), 0.5/2 μg/ml (ceftar...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00389-17
更新日期:2017-07-25 00:00:00
abstract::Pentamidine is a second-line agent in the treatment of leishmaniasis whose mode of action and resistance mechanism are not well understood. In this work, we show that the intracellular ABC protein PRP1 (pentamidine resistance protein 1) (ABCC7) can confer resistance to pentamidine in Leishmania sp. parasites in the in...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00404-07
更新日期:2007-08-01 00:00:00
abstract::The in vitro activities of two new carboxyquinolones, A-56619 (difloxacin) and A-56620, were compared with those of ciprofloxacin, norfloxacin, and ofloxacin against genital tract pathogens. All the quinolones were highly active against Neisseria gonorrhoeae. A-56619 had the lowest MICs against Chlamydia trachomatis (...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.30.6.948
更新日期:1986-12-01 00:00:00
abstract::Candida albicans and Staphylococcus aureus form vigorous polymicrobial biofilms in serum, which may serve as the source of coinfection in patients. More importantly, S. aureus is highly resistant to vancomycin during polymicrobial biofilm formation, with no decreases in bacterial viability observed with up to 1,600 mi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00573-10
更新日期:2010-09-01 00:00:00
abstract::Bacterial susceptibility to a new organic acid related to nalidixic acid and oxolinic acid was tested. The in vitro susceptibility pattern of the new compound was found to be very similar to that of nalidixic acid. ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.13.3.533
更新日期:1978-03-01 00:00:00
abstract::The present study confirms that CBA/J mice are susceptible to several clinical isolates of Streptococcus pneumoniae, including four of five penicillin-susceptible and all five penicillin-resistant strains tested, thus providing the first noncompromised animal model for penicillin-resistant S. pneumoniae pneumonia. In ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.6.1520
更新日期:1996-06-01 00:00:00
abstract::The MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation o...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/AAC.01940-16
更新日期:2017-01-24 00:00:00
abstract::Ten beta-lactamase-producing Enterococcus faecalis isolates were examined for the presence of the staphylococcal beta-lactamase repressor and antirepressor genes. Four isolates, previously shown to be unrelated to each other by pulsed-field gel electrophoresis analysis, were positive for both genes by PCR, although be...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.5.1170
更新日期:1996-05-01 00:00:00
abstract::The complete sequence of the carbapenem-resistance-conferring conjugative plasmid pLD209 from a Pseudomonas putida clinical strain is presented. pLD209 is formed by 3 well-defined regions: an adaptability module encompassing a Tn402-like class 1 integron of clinical origin containing blaVIM-2 and aacA4 gene cassettes,...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02494-13
更新日期:2014-01-01 00:00:00
abstract::SM-7338, a new carbapenem antibiotic, was demonstrated to have potent antibacterial activity against a broad spectrum of aerobes, including Staphylococcus aureus, beta-hemolytic streptococci, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria spp., members of the family Enterobacteriaceae, Pseudomonas spp., a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.2.215
更新日期:1989-02-01 00:00:00
abstract::Kill-kinetic methods were used to provide data on the bactericidal activity of subinhibitory (0.5x MIC), inhibitory (1x MIC), and suprainhibitory (4x MIC) concentrations of LY146032 against methicillin-susceptible and -resistant Staphylococcus aureus and Staphylococcus epidermidis. These bactericidal activities were c...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.31.8.1210
更新日期:1987-08-01 00:00:00
abstract::We present case histories of four patients treated with artemether-lumefantrine for falciparum malaria in UK hospitals in 2015 to 2016. Each subsequently presented with recurrent symptoms and Plasmodium falciparum parasitemia within 6 weeks of treatment with no intervening travel to countries where malaria is endemic....
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02382-16
更新日期:2017-02-23 00:00:00
abstract::A Staphylococcus aureus surveillance program was initiated in the United States to examine the in vitro activity of ceftaroline and epidemiologic trends. Susceptibility testing by Clinical and Laboratory Standards Institute broth microdilution was performed on 4,210 clinically significant isolates collected in 2009 fr...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00315-11
更新日期:2011-09-01 00:00:00
abstract::Seventy-one strains of 15 species of rapidly growing mycobacteria were studied for their susceptibilities to fatty acids with 2 to 20 carbons by the agar dilution method at pH 7.0. Most mycobacteria other than potential pathogens (Mycobacterium fortuitum and Mycobacterium chelonei) were resistant to saturated fatty ac...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.26.2.164
更新日期:1984-08-01 00:00:00
abstract::Meningococcal gyrA gene sequence data, MICs, and mouse infection were used to define the ciprofloxacin breakpoint for Neisseria meningitidis. Residue T91 or D95 of GyrA was altered in all meningococcal isolates with MICs of ≥ 0.064 μg/ml but not among isolates with MICs of ≤ 0.032 μg/ml. Experimental infection of cipr...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02184-12
更新日期:2013-04-01 00:00:00