Crystal structure and activity studies of the Mycobacterium tuberculosis beta-lactamase reveal its critical role in resistance to beta-lactam antibiotics.

Abstract:

:beta-Lactam antibiotics are extremely effective in disrupting the synthesis of the bacterial cell wall in both gram-positive and gram-negative bacteria. However, they are ineffective against Mycobacterium tuberculosis, due to the production of a beta-lactamase enzyme encoded on the chromosome of M. tuberculosis that degrades these antibiotics. Indeed, recent studies have demonstrated that deletion of the blaC gene, the only gene encoding a beta-lactamase in M. tuberculosis, or inhibition of the encoded enzyme resulted in significantly increased sensitivity to beta-lactam antibiotics. In this paper we present a biochemical and structural characterization of M. tuberculosis BlaC. Recombinant BlaC shows a broad range of specificity with almost equal penicillinase and cepholothinase activity. While clavulanate is a mechanism-based inhibitor to class A beta-lactamase with high potency (typically K(i) < 0.1 microM), it is a relatively poor inhibitor of the M. tuberculosis BlaC (K(i) = 2.4 microM). The crystal structure of the enzyme, determined at a resolution of 1.7 A, shows that the overall fold of the M. tuberculosis enzyme is similar to other class A beta-lactamases. There are, however, several distinct features of the active site, such as the amino acid substitutions N132G, R164A, R244A, and R276E, that explain the broad specificity of the enzyme, relatively low penicillinase activity, and resistance to clavulanate.

authors

Wang F,Cassidy C,Sacchettini JC

doi

10.1128/AAC.00320-06

subject

Has Abstract

pub_date

2006-08-01 00:00:00

pages

2762-71

issue

8

eissn

0066-4804

issn

1098-6596

pii

50/8/2762

journal_volume

50

pub_type

杂志文章
  • Sequential emergence of antibiotic resistance in enterococcal bloodstream isolates over 25 years.

    abstract::We determined the antibiotic susceptibilities of 1,785 enterococcal bloodstream isolates collected over 25 years. Antibiotic resistance emerged at a greater rate in Enterococcus faecium than in other enterococcal species, and E. faecium isolates became proportionally more common over time. Our findings confirm the pat...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.46.11.3676-3678.2002

    authors: Murdoch DR,Mirrett S,Harrell LJ,Monahan JS,Reller LB

    更新日期:2002-11-01 00:00:00

  • Pharmacokinetic and pharmacodynamic study of the human immunodeficiency virus protease inhibitor amprenavir after multiple oral dosing.

    abstract::In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 临床试验,杂志文章

    doi:10.1128/AAC.45.1.30-37.2001

    authors: Sadler BM,Gillotin C,Lou Y,Stein DS

    更新日期:2001-01-01 00:00:00

  • Ciprofloxacin interactions with imipenem and amikacin against multiresistant Pseudomonas aeruginosa.

    abstract::In vitro interactions of ciprofloxacin with imipenem and amikacin were evaluated by the killing-curve technique against 26 Pseudomonas aeruginosa strains resistant to amikacin and resistant or moderately susceptible to ciprofloxacin and imipenem. Imipenem enhanced killing by ciprofloxacin in tests with 11 strains, whe...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.31.6.959

    authors: Giamarellou H,Petrikkos G

    更新日期:1987-06-01 00:00:00

  • Characterization of rpsL and rrs mutations in streptomycin-resistant Mycobacterium tuberculosis isolates from diverse geographic localities.

    abstract::Two genes (rpsL and rrs) with mutations associated with streptomycin resistance in Mycobacterium tuberculosis were characterized in 78 streptomycin-resistant and 61 streptomycin-susceptible isolates recovered from patients living in the United States, South America, Europe, Africa, and Asia. Fifty-four percent of the ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.40.4.1024

    authors: Sreevatsan S,Pan X,Stockbauer KE,Williams DL,Kreiswirth BN,Musser JM

    更新日期:1996-04-01 00:00:00

  • Erythromycin resistance in Borrelia burgdorferi.

    abstract::Susceptibility testing of laboratory strains and clinical isolates of Borrelia burgdorferi indicates that resistance to erythromycin is present in them. Evaluation of the MICs, minimal bactericidal concentrations, and kinetics of bacterial killing of erythromycin suggests that this resistance is increased by preexposu...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.46.11.3637-3640.2002

    authors: Terekhova D,Sartakova ML,Wormser GP,Schwartz I,Cabello FC

    更新日期:2002-11-01 00:00:00

  • First detection of metallo-beta-lactamase VIM-2 in Pseudomonas aeruginosa isolates from Colombia.

    abstract::Carbapenem resistance rates in Pseudomonas aeruginosa isolates in Colombia, as in many South American countries, are high for reasons that remain unclear. From our nationwide network, we describe the first detection of the metallo-beta-lactamase VIM-2 in clinical isolates of P. aeruginosa from multiple cities within C...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.50.1.226-229.2006

    authors: Villegas MV,Lolans K,del Rosario Olivera M,Suarez CJ,Correa A,Queenan AM,Quinn JP,Colombian Nosocomial Resistance Study Group.

    更新日期:2006-01-01 00:00:00

  • Identification of chromosomal antibiotic resistance genes in Streptococcus anginosus ("S. milleri").

    abstract::Determinants encoding resistance to antibiotics, except penicillin, of 5 of 21 Streptococcus anginosus clinical isolates that we examined transferred by conjugation into Enterococcus faecalis and into 1 to 5 streptococcal recipients at frequencies of 10(-6) to 10(-8) transconjugants per donor. No R plasmids were detec...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.34.9.1685

    authors: Clermont D,Horaud T

    更新日期:1990-09-01 00:00:00

  • Virulence factors of Escherichia coli isolates that produce CTX-M-type extended-spectrum beta-lactamases.

    abstract::This study determined the phylogenetic groups and virulence factors of 37 Escherichia coli isolates producing types of CTX-M compared with those of 19 isolates producing different types of extended-spectrum beta-lactamases (ESBLs) in a well-defined North American population. Most CTX-M-14 producers (97%) were from phy...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.49.11.4667-4670.2005

    authors: Pitout JD,Laupland KB,Church DL,Menard ML,Johnson JR

    更新日期:2005-11-01 00:00:00

  • Pharmacokinetics of cefamandole in patients with renal impairment.

    abstract::Cefamandole pharmacokinetics were investigated in 24 adult males with stable renal function and creatinine clearances of 0 to 139 ml/min. After intramuscular injection of 1.0 g of cefamandole, peak plasma concentrations were achieved between 1 and 2 h. Maximum plasma concentration and drug half-life increased as creat...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.15.2.161

    authors: Czerwinski AW,Pederson JA

    更新日期:1979-02-01 00:00:00

  • In vitro activity of wALADin benzimidazoles against different life cycle stages of Plasmodium parasites.

    abstract::wALADin1 benzimidazoles are specific inhibitors of δ-aminolevulinic acid dehydratase from Wolbachia endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage Plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 μM, respectively). One of these derivat...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02383-14

    authors: Lentz CS,Sattler JM,Fendler M,Gottwalt S,Halls VS,Strassel S,Arriens S,Hannam JS,Specht S,Famulok M,Mueller AK,Hoerauf A,Pfarr KM

    更新日期:2015-01-01 00:00:00

  • Action of polymyxin B on bacterial membranes: morphological changes in the cytoplasm and in the outer membrane of Salmonella typhimurium and Escherichia coli B.

    abstract::Though the primary action of the cationic antibiotic polymyxin B is against the membrane of susceptible bacteria, severe morphological changes are detected in the cytoplasm. Using fluorescence microscopy and a mono-N-dansyl-polymyxin B derivative, we could demonstrate aggregations of the antibiotic with cellular mater...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.8.1.95

    authors: Schindler PR,Teuber M

    更新日期:1975-07-01 00:00:00

  • Chimeric Cyanovirin-MPER recombinantly engineered proteins cause cell-free virolysis of HIV-1.

    abstract::Human immunodeficiency virus (HIV) is the primary etiologic agent responsible for the AIDS pandemic. In this work, we used a chimeric recombinant protein strategy to test the possibility of irreversibly destroying the HIV-1 virion using an agent that simultaneously binds the Env protein and viral membrane. We construc...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00309-13

    authors: Contarino M,Bastian AR,Kalyana Sundaram RV,McFadden K,Duffy C,Gangupomu V,Baker M,Abrams C,Chaiken I

    更新日期:2013-10-01 00:00:00

  • Occidiofungin's chemical stability and in vitro potency against Candida species.

    abstract::Occidiofungin is a cyclic glyco-lipopeptide produced by Burkholderia contaminans. MICs against Candida species were between 0.5 and 2.0 μg/ml. Occidiofungin retains its in vitro potency in the presence of 5% and 50% human serum with a minimal lethal concentration (MLC) of 2 and 4 μg/ml, respectively. Time-kill and pos...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.05231-11

    authors: Ellis D,Gosai J,Emrick C,Heintz R,Romans L,Gordon D,Lu SE,Austin F,Smith L

    更新日期:2012-02-01 00:00:00

  • In vivo activity of ajoene against rodent malaria.

    abstract::Ajoene (4,5,9-trithiadodeca-1,6,11-triene 9-oxide), a product initially isolated from extracts of garlic (Allium sativum), was tested for its antimalarial activity in vivo in a well-characterized murine model. A single ajoene dose of 50 mg/kg, on the day of infection, suppressed the development of parasitemia; there w...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.38.2.337

    authors: Perez HA,De la Rosa M,Apitz R

    更新日期:1994-02-01 00:00:00

  • β-Lactam resistance in methicillin-resistant Staphylococcus aureus USA300 is increased by inactivation of the ClpXP protease.

    abstract::Methicillin-resistant Staphylococcus aureus (MRSA) has acquired the mecA gene encoding a peptidoglycan transpeptidase, penicillin binding protein 2a (PBP2a), which has decreased affinity for β-lactams. Quickly spreading and highly virulent community-acquired (CA) MRSA strains recently emerged as a frequent cause of in...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.02802-14

    authors: Bæk KT,Gründling A,Mogensen RG,Thøgersen L,Petersen A,Paulander W,Frees D

    更新日期:2014-08-01 00:00:00

  • Decline in sulfadoxine-pyrimethamine-resistant alleles after change in drug policy in the Amazon region of Peru.

    abstract::The frequency of alleles with triple mutations conferring sulfadoxine-pyrimethamine (SP) resistance in the Peruvian Amazon Basin has declined (16.9% for dhfr and 0% for dhps compared to 47% for both alleles in 1997) 5 years after SP was replaced as the first-line treatment for Plasmodium falciparum malaria. Microsatel...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00975-07

    authors: Zhou Z,Griffing SM,de Oliveira AM,McCollum AM,Quezada WM,Arrospide N,Escalante AA,Udhayakumar V

    更新日期:2008-02-01 00:00:00

  • DNA sequence variation within vanA, vanB, vanC-1, and vanC-2/3 genes of clinical Enterococcus isolates.

    abstract::We studied the DNA sequence variation of van genes of 34 isolates of Enterococcus spp. The isolates containing the vanB gene exhibited between 0 and 41 base pair changes per 801 bp studied when the vanB sequences were compared to that of the reference strain Enterococcus faecalis V583. The isolates carrying the vanC-2...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.42.1.202

    authors: Patel R,Uhl JR,Kohner P,Hopkins MK,Steckelberg JM,Kline B,Cockerill FR 3rd

    更新日期:1998-01-01 00:00:00

  • Meropenem pharmacokinetics and penetration into an inflammatory exudate.

    abstract::The pharmacokinetics and penetration into a cantharidine-induced inflammatory exudate of meropenem was studied in six volunteers following a single 1-g intravenous dose. Concentrations in plasma, urine, and the inflammatory exudate were determined by a microbiological assay. The mean elimination half-life of meropenem...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.34.8.1515

    authors: Wise R,Logan M,Cooper M,Ashby JP,Andrews JM

    更新日期:1990-08-01 00:00:00

  • Desbutyl-benflumetol, a novel antimalarial compound: in vitro activity in fresh isolates of Plasmodium falciparum from Thailand.

    abstract::Desbutyl-benflumetol (DBB) is a novel antimalarial compound closely related to benflumetol (lumefantrine), of which it is a putative metabolite. The in vitro response of Plasmodium falciparum to DBB was studied in Mae Hong Son and Mae Sot, in northwest Thailand, in 1997 and 1998. In total, 155 fresh isolates were succ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.45.7.2106-2109.2001

    authors: Noedl H,Allmendinger T,Prajakwong S,Wernsdorfer G,Wernsdorfer WH

    更新日期:2001-07-01 00:00:00

  • Integron-mediated rifampin resistance in Pseudomonas aeruginosa.

    abstract::A new rifampin resistance gene, arr-2, has been found in Pseudomonas aeruginosa. The ARR-2 protein shows 54% amino acid identity to the rifampin ADP-ribosylating transferase encoded by the arr gene from Mycobacterium smegmatis. This arr-2 gene is located on a gene cassette within a class I integron. ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.43.4.960

    authors: Tribuddharat C,Fennewald M

    更新日期:1999-04-01 00:00:00

  • In vitro and in vivo antibacterial activities of K-4619, a new semisynthetic aminoglycoside.

    abstract::The antibacterial activities of K-4619 (3-de-O-methylsporaricin A sulfate) were compared with those of sporaricin A, amikacin, dibekacin, and gentamicin. K-4619 exhibited a high order of activity against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa. Its activity against Providencia specie...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.26.2.187

    authors: Saino Y,Hattori Y,Koshi T,Kobayashi F,Oda T,Mitsuhashi S

    更新日期:1984-08-01 00:00:00

  • Novel HIV-1 protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV-1 variants.

    abstract::We identified GRL-1388 and -1398, potent nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran (Tp-THF). GRL-1388 was as potent as darunavir (DRV) against various drug-resistant HIV-1 laboratory strains with 50% ef...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01540-10

    authors: Ide K,Aoki M,Amano M,Koh Y,Yedidi RS,Das D,Leschenko S,Chapsal B,Ghosh AK,Mitsuya H

    更新日期:2011-04-01 00:00:00

  • Investigation of Multiple Resistance Mechanisms in Voriconazole-Resistant Aspergillus flavus Clinical Isolates from a Chest Hospital Surveillance in Delhi, India.

    abstract::Invasive and allergic infections by Aspergillus flavus are more common in tropical and subtropical countries. The emergence of voriconazole (VRC) resistance in A. flavus impacts the management of aspergillosis, as azoles are used as the first-line and empirical therapy. We screened 120 molecularly confirmed A. flavus ...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.01928-17

    authors: Sharma C,Kumar R,Kumar N,Masih A,Gupta D,Chowdhary A

    更新日期:2018-02-23 00:00:00

  • A cell-based strategy to assess intrinsic inhibition efficiencies of HIV-1 reverse transcriptase inhibitors.

    abstract::During HIV-1 reverse transcription, there are increasing opportunities for nucleos(t)ide (NRTI) or nonnucleoside (NNRTI) reverse transcriptase (RT) inhibitors to stop elongation of the nascent viral DNA (vDNA). In addition, RT inhibitors appear to influence the kinetics of vDNA synthesis differently. While cell-free k...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.04163-14

    authors: Abram ME,Tsiang M,White KL,Callebaut C,Miller MD

    更新日期:2015-02-01 00:00:00

  • Two 2-hydroxy-3-alkyl-1,4-naphthoquinones with in vitro and in vivo activities against Toxoplasma gondii.

    abstract::Two 3-alkyl-substituted 2-hydroxy-1,4-naphthoquinones, NSC 113452 (NSC52) and NSC 113455 (NSC55), were evaluated for activity against Toxoplasma gondii in vitro and in murine models of acute toxoplasmosis. In vitro, both NSC52 and NSC55 significantly inhibited intracellular replication of T. gondii. In vivo, each comp...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.42.9.2284

    authors: Khan AA,Nasr M,Araujo FG

    更新日期:1998-09-01 00:00:00

  • Amikacin Inhalation as Salvage Therapy for Refractory Nontuberculous Mycobacterial Lung Disease.

    abstract::Although guidelines recommend amikacin (AMK) inhalation therapy for difficult-to-treat nontuberculous mycobacterial lung disease (NTM-LD), data are limited regarding the safety and clinical efficacy of this salvage therapy. We retrospectively evaluated the treatment outcomes of 77 patients with refractory NTM-LD cause...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00011-18

    authors: Jhun BW,Yang B,Moon SM,Lee H,Park HY,Jeon K,Kwon OJ,Ahn J,Moon IJ,Shin SJ,Daley CL,Koh WJ

    更新日期:2018-06-26 00:00:00

  • Efficacy of a hydroxynaphthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis.

    abstract::The efficacy of a new class of drugs for Pneumocystis carinii pneumonitis was demonstrated. 566C80, a hydroxynaphthoquinone, administered orally in a dose of greater than or equal to 100 mg/kg of body weight per day prophylactically prevented P. carinii pneumonitis in 90% or more of rats, while all untreated control a...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.34.2.225

    authors: Hughes WT,Gray VL,Gutteridge WE,Latter VS,Pudney M

    更新日期:1990-02-01 00:00:00

  • Activity of ribavirin against Hantaan virus correlates with production of ribavirin-5'-triphosphate, not with inhibition of IMP dehydrogenase.

    abstract::Ribavirin (RBV) is a broad-spectrum antiviral agent that inhibits the production of infectious Hantaan virus (HTNV). Although the mechanism of action of RBV against HTNV is not understood, RBV is metabolized in human cells to both RBV-5'-monophosphate, which inhibits IMP dehydrogenase, resulting in a decrease in intra...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/AAC.00790-06

    authors: Sun Y,Chung DH,Chu YK,Jonsson CB,Parker WB

    更新日期:2007-01-01 00:00:00

  • Distribution of azithromycin in plasma and tonsil tissue after repeated oral administration of 10 or 20 milligrams per kilogram in pediatric patients.

    abstract::Azithromycin concentrations in the tonsils of 56 pediatric patients, treated with 10 or 20 mg of the drug per kg of body weight for 3 days, were compared. Azithromycin levels in plasma and tonsil samples were determined up to 8.5 days after the last dose. The 20-mg/kg regimen resulted in an improved tonsillar distribu...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 临床试验,杂志文章

    doi:10.1128/aac.46.5.1594-1596.2002

    authors: Blandizzi C,Malizia T,Batoni G,Ghelardi E,Baschiera F,Bruschini P,Senesi S,Campa M,Del Tacca M

    更新日期:2002-05-01 00:00:00

  • Polycationic biocides with pendant active groups: molecular weight dependence of antibacterial activity.

    abstract::Two types of polycations with pendant active groups were synthesized: one is polymethacrylate containing pendant biguanide units, and the other is poly(vinylbenzyl ammonium chloride). The two polycations were found to exhibit higher bactericidal activity against Staphylococcus aureus than the corresponding monomers. F...

    journal_title:Antimicrobial agents and chemotherapy

    pub_type: 杂志文章

    doi:10.1128/aac.30.1.132

    authors: Ikeda T,Hirayama H,Yamaguchi H,Tazuke S,Watanabe M

    更新日期:1986-07-01 00:00:00