Abstract:
:Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid transporter of Mycobacterium tuberculosis In the present study, we characterized indoleamide effects on bacterial cell morphology and reevaluated pharmacokinetics and in vivo efficacy using an optimized oral formulation. Morphologically, indoleamide-treated M. tuberculosis cells demonstrated significantly higher numbers of dimples near the poles or septum, which may serve as the mechanism of cell death for this bactericidal scaffold. Using the optimized formulation, an expanded-spectrum indoleamide, compound 2, showed significantly improved pharmacokinetic (PK) parameters and in vivo efficacy in mouse infection models. In a comparative study, compound 2 showed superior efficacy over compound 3 (NITD-304) in a high-dose aerosol mouse infection model. Since indoleamides are equally active on drug-resistant M. tuberculosis, these findings demonstrate the therapeutic potential of this novel scaffold for the treatment of both drug-susceptible and drug-resistant tuberculosis.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Lun S,Tasneen R,Chaira T,Stec J,Onajole OK,Yang TJ,Cooper CB,Mdluli K,Converse PJ,Nuermberger EL,Raj VS,Kozikowski A,Bishai WRdoi
10.1128/AAC.00343-19subject
Has Abstractpub_date
2019-06-24 00:00:00issue
7eissn
0066-4804issn
1098-6596pii
AAC.00343-19journal_volume
63pub_type
杂志文章abstract::Triazoles are first-line agents for treating aspergillosis. The prevalence of azole resistance in Aspergillus fumigatus is increasing, and cross-resistance is a growing concern. In this study, the susceptibilities of 40 A. fumigatus clinical isolates were tested by using the CLSI method with amphotericin B, itraconazo...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01141-13
更新日期:2013-11-01 00:00:00
abstract::In a retrospective review of 24 patients with histoplasmosis, blastomycosis, or coccidioidomycosis treated with voriconazole (most for salvage therapy), the outcome was favorable (improved or stable) for 22 (95.8%) within 2 months of starting voriconazole and for 20 (83.3%) at the last follow-up. Prospective studies a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01148-07
更新日期:2009-04-01 00:00:00
abstract::Boronic acid transition state inhibitors (BATSIs) with R1 side chains of cefotaxime and ceftazidime were assayed against SHV-1, SHV-2, SHV-5, D104K, and D104K G238S beta-lactamases. The D104K variant was the most susceptible to inhibition by the ceftazidime BATSI (Ki, 730+/-80 nM), while the D104K G238S variant was th...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01293-06
更新日期:2007-04-01 00:00:00
abstract::Hepatitis C virus (HCV) inhibitors include direct-acting antivirals (DAAs) such as NS3 serine protease inhibitors, nucleoside and nonnucleoside polymerase inhibitors, and host-targeting antivirals (HTAs) such as cyclophilin inhibitors that have been developed in recent years. Drug-resistant HCV variants have been repo...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00294-11
更新日期:2011-09-01 00:00:00
abstract::Group A streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, ranging from mild throat and skin infections to severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), a dextrorotatory morphinan and a widely used antituss...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00950-10
更新日期:2011-03-01 00:00:00
abstract::The elimination kinetics of cefotetan (YM09330), a new parenteral semisynthetic cephamycin derivative, were studied in eight healthy volunteers and 41 patients with renal insufficiency after the administration of a single 500-mg dose intravenously. Concentrations of cefotetan in serum and urine were determined by both...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.23.1.31
更新日期:1983-01-01 00:00:00
abstract::A radioimmunoassay system has been developed for the measurement of two major metabolites of 9,3"-diacetylmidecamycin, Mb-6 and Mb-12. A radioimmunoassay for Mb-6 was performed by using anti-Mb-6 serum and a [125I]tyramined Mb-6 derivative as a radiolabeled antigen. The labeled antigen was prepared by the chloramine T...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.22.6.976
更新日期:1982-12-01 00:00:00
abstract::Two ceftazidime-resistant variants of Pseudomonas aeruginosa (PA-48, PA-60), obtained from cardiac vegetations of rabbits with endocarditis receiving ceftazidime therapy, were studied for mechanisms of resistance. Both resistant variants were stably derepressed for the type Id beta-lactamase, which was ceftazidime ind...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.31.2.253
更新日期:1987-02-01 00:00:00
abstract::The effect of 19 antimicrobial agents on human polymorphonuclear leukocyte function was evaluated by chemiluminescence assays, yeast phagocytosis and killing, and lactate dehydrogenase release. Tetracycline and trimethoprim inhibited chemiluminescence and reduced killing at therapeutic concentrations of 2 microgram/ml...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.20.1.15
更新日期:1981-07-01 00:00:00
abstract::Hypermutable Pseudomonas aeruginosa strains are found with high frequency in the lungs of patients with chronic infections and are associated with high antibiotic resistance rates. The in vivo consequences of hypermutation for treatment in a mouse model of lung infection using strain PAO1 and its hypermutable derivati...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.50.3.975-983.2006
更新日期:2006-03-01 00:00:00
abstract::Magainins are novel polycationic peptides with broad-spectrum antimicrobial activity, including activity against gram-negative bacteria. Gram-negative bacteremia can elicit endotoxic shock that is associated with the increased formation of eicosanoids. Inhibition of eicosanoid synthesis has been shown to improve the o...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.3.393
更新日期:1993-03-01 00:00:00
abstract::Ampicillin, trimethoprim-sulfamethoxazole, mecillinam, nitrofurantoin, and ciprofloxacin mean resistance rates for 2,000 urinary tract isolates collected from outpatients across Canada in 1998 were 41.1, 19.2, 14.7, 5.0, and 1.8%, respectively. For Escherichia coli isolates alone (n = 1,681) comparable rates were 41. ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.4.1089-1092.2000
更新日期:2000-04-01 00:00:00
abstract::In determining the quality control limits for the Clinical Laboratory Standards Institute-recommended quality control organisms with tigecycline, a number of inconsistencies in the results were encountered that appeared to be related to the age of the Mueller-Hinton broth II. This study was performed to examine the ef...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.49.9.3910-3918.2005
更新日期:2005-09-01 00:00:00
abstract::Various Pseudomonas aeruginosa PAO1 NfxB mutants were isolated on agar plates containing cefpirome and ofloxacin. They were classified into type A and type B, based on the degrees of changes in their susceptibilities. Type A mutants were four to eight times more resistant to ofloxacin, erythromycin, and new zwitterion...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.4.909
更新日期:1996-04-01 00:00:00
abstract::In separate previous studies, we have shown that lipid-complexed amphotericin B (Abelcet [ABLC]) and liposomal amphotericin B (AmBisome [AmBi]) are efficacious against coccidioidal meningitis in rabbits. Here, we compared ABLC and AmBi directly in a coccidioidal meningitis model. Male New Zealand White rabbits were in...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01538-08
更新日期:2009-05-01 00:00:00
abstract::Sulfide production has been proposed to be a universal defense mechanism against antibiotics in bacteria (K. Shatalin, E. Shatalina, A. Mironov, and E. Nudler, Science 334:986-990, 2011, doi:10.1126/science.1209855). To gain insight into the mechanism underlying sulfide protection, we systematically and comparatively ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00602-18
更新日期:2018-09-24 00:00:00
abstract::The biosynthetic gene cluster of lankamycin (LM), a 14-member macrolide antibiotic, is encoded on the 210-kb linear plasmid pSLA2-L in Streptomyces rochei 7434AN4. LM contains a 3-hydroxy-2-butyl group at the C-13 position, which is different from an ethyl group in erythromycin. The following two possibilities could b...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00016-06
更新日期:2006-06-01 00:00:00
abstract::WR99210, a dihydrofolate reductase inhibitor, has promising in vitro activity against Mycobacterium avium complex (MAC). The in vitro activities of WR99210 alone and in combination with a fixed concentration of dapsone (0.5 microgram/ml) were evaluated against 35 clinical MAC isolates by a broth dilution method. The M...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.40.11.2644
更新日期:1996-11-01 00:00:00
abstract::Respiratory syncytial virus (RSV) causes serious illness (lower respiratory illness) in preterm infants. RSV antibody-enriched immunoglobulin (RSVIG) that was lyophilized (LYO) protected against RSV lower respiratory illness. The Food and Drug Administration now requires an additional viral inactivation step (VI). We ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1128/aac.39.3.668
更新日期:1995-03-01 00:00:00
abstract::A novel plasmid-borne resistance gene cluster comprising the genes erm(T) for macrolide-lincosamide-streptogramin B resistance, dfrK for trimethoprim resistance, and tet(L) for tetracycline resistance was identified in a porcine methicillin-resistant Staphylococcus aureus sequence type 398 (ST398) strain. This erm(T)-...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01091-09
更新日期:2010-02-01 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::Antibiotic therapy is the most commonly used strategy to control pathogenic infections; however, it has contributed to the generation of antibiotic-resistant bacteria. To circumvent this emerging problem, we are searching for compounds that target bacterial virulence factors rather than their viability. Pseudomonas ae...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00732-11
更新日期:2012-01-01 00:00:00
abstract::A PCR-based technique using new fluorescent probes, called molecular beacons, was developed to detect the antifolate resistance-associated S108N point mutation in Plasmodium falciparum. One hundred African clinical isolates were tested by the new method in comparison with the PCR-restriction fragment length polymorphi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.12.3461-3464.2000
更新日期:2000-12-01 00:00:00
abstract::Miltefosine (MT) is a membrane-active alkylphospholipid licensed for the topical treatment of breast cancer skin metastases and the oral treatment of leishmaniasis, although its mechanism of action remains unclear. Electron paramagnetic resonance (EPR) spectroscopy of a spin-labeled lipid and a thiol-specific spin lab...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01332-13
更新日期:2014-06-01 00:00:00
abstract::The efficacy of clarithromycin in a murine model of acute toxoplasmosis was studied. Clarithromycin was administered alone and concurrently with minocycline, and efficacy was assessed by survival rates and sequential determination of parasite burden in blood, brains, and lungs. Limited protection resulted from adminis...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.12.2852
更新日期:1992-12-01 00:00:00
abstract::The VanR-VanS two-component system is responsible for inducing resistance to glycopeptide antibiotics in various bacteria. We have performed a comparative study of the VanR-VanS systems from two streptomyces strains, Streptomyces coelicolor and Streptomyces toyocaensis, to characterize how the two proteins cooperate t...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01367-15
更新日期:2015-12-28 00:00:00
abstract::Resistance to ceftazidime, detected in isolates of Escherichia coli 5518 and Enterobacter gergoviae 3773 from our hospital, was transferred, together with resistance to aminoglycosides, trimethoprim, sulfonamide, and other beta-lactam antibiotics, by conjugation to E. coli JP559. Both E. coli transconjugants were resi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.38.12.2838
更新日期:1994-12-01 00:00:00
abstract::C-8-methoxy fluoroquinolones were more lethal than C-8-bromine, C-8-ethoxy, and C-8-H derivatives for Staphylococcus aureus, especially when topoisomerase IV was resistant. The methoxy group also increased lethality against wild-type cells when protein synthesis was inhibited. These properties encourage refinement of ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.42.4.956
更新日期:1998-04-01 00:00:00
abstract::Mycobactin biosynthesis in Mycobacterium tuberculosis facilitates iron acquisition, which is required for growth and virulence. The mycobactin biosynthesis inhibitor salicyl-AMS [5'-O-(N-salicylsulfamoyl)adenosine] inhibits M. tuberculosis growth in vitro under iron-limited conditions. Here, we conducted a single-dose...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00918-13
更新日期:2013-10-01 00:00:00
abstract::Lung infections caused by Mycobacterium abscessus are emerging as a global threat to individuals with cystic fibrosis and to other patient groups. Recent evidence for human-to-human transmission worsens the situation. M. abscessus is an intrinsically multidrug-resistant pathogen showing resistance to even standard ant...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00155-17
更新日期:2017-05-24 00:00:00