Abstract:
:The Cpx stress response is widespread among Enterobacteriaceae We previously reported a mutation in cpxA in a multidrug-resistant strain of Klebsiella aerogenes isolated from a patient treated with imipenem. This mutation yields a single-amino-acid substitution (Y144N) located in the periplasmic sensor domain of CpxA. In this work, we sought to characterize this mutation in Escherichia coli by using genetic and biochemical approaches. Here, we show that cpxAY144N is an activated allele that confers resistance to β-lactams and aminoglycosides in a CpxR-dependent manner, by regulating the expression of the OmpF porin and the AcrD efflux pump, respectively. We also demonstrate the effect of the intimate interconnection between the Cpx system and peptidoglycan integrity on the expression of an exogenous AmpC β-lactamase by using imipenem as a cell wall-active antibiotic or by inactivating penicillin-binding proteins. Moreover, our data indicate that the Y144N substitution abrogates the interaction between CpxA and CpxP and increases phosphotransfer activity on CpxR. Because the addition of a strong AmpC inducer such as imipenem is known to cause abnormal accumulation of muropeptides (disaccharide-pentapeptide and N-acetylglucosamyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamy-meso-diaminopimelic-acid-d-alanyl-d-alanine) in the periplasmic space, we propose these molecules activate the Cpx system by displacing CpxP from the sensor domain of CpxA. Altogether, these data could explain why large perturbations to peptidoglycans caused by imipenem lead to mutational activation of the Cpx system and bacterial adaptation through multidrug resistance. These results also validate the Cpx system, in particular, the interaction between CpxA and CpxP, as a promising therapeutic target.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Masi M,Pinet E,Pagès JMdoi
10.1128/AAC.00291-20subject
Has Abstractpub_date
2020-05-21 00:00:00issue
6eissn
0066-4804issn
1098-6596pii
AAC.00291-20journal_volume
64pub_type
杂志文章abstract::(E)-(S)-4-((S)-2-{3-[(5-methyl-isoxazole-3-carbonyl)-amino]-2-oxo-2H-pyridin-1-yl}-pent-4-ynoylamino)-5-((S)-2-oxo-pyrrolidin-3-yl)-pent-2-enoic acid ethyl ester (Compound 1) is a novel, irreversible inhibitor of human rhinovirus (HRV) 3C protease {inactivation rate constant (Kobs/[I]) of 223,000 M-1s-1}. In cell-base...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/AAC.49.6.2267-2275.2005
更新日期:2005-06-01 00:00:00
abstract::Horizontal transfer of plasmids encoding antimicrobial resistance and virulence determinants has been instrumental in Staphylococcus aureus evolution, including the emergence of community-associated methicillin-resistant S. aureus (CA-MRSA). In the early 1990s, the first CA-MRSA strain isolated in Western Australia (W...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01560-19
更新日期:2019-10-22 00:00:00
abstract::The effects of cefodizime and cefuroxime on neutrophil phagocytosis and reactive oxygen production in 54 patients undergoing elective coronary artery bypass grafting were studied. Both drugs were administered twice at a dosage of 40 mg/kg of body weight (pre- and intraoperative). Phagocytic capacity was assessed by me...
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.41.7.1584
更新日期:1997-07-01 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
doi:10.1128/AAC.42.7.1659
更新日期:1998-07-01 00:00:00
abstract::The antiviral activity of a new series of thymidine analogs was determined against vaccinia virus (VV), cowpox virus (CV), herpes simplex virus, and varicella-zoster virus. Several compounds were identified that had good activity against each of the viruses, including a set of novel 5-substituted deoxyuridine analogs....
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01447-06
更新日期:2007-05-01 00:00:00
abstract::Against 307 pneumococci of various resistotypes, dalbavancin MICs were 0.008 to 0.125 microg/ml. All strains were susceptible to vancomycin, teicoplanin, linezolid, and quinupristin-dalfopristin. Dalbavancin at 2x MIC was bactericidal against all 10 pneumococci tested after 24 h. Vancomycin and teicoplanin killed 10 a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.49.12.5182-5184.2005
更新日期:2005-12-01 00:00:00
abstract::A series of 1-cyclopropyl-8-methoxy-quinazoline-2,4-diones was synthesized and evaluated for lowering the ratio of the antimicrobial MIC in gyrase resistance mutants to that in the gyr(+) (wild type) using isogenic strains of Escherichia coli. Dione features that lowered this ratio were a 3-amino group and C-7 ring st...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00330-08
更新日期:2008-11-01 00:00:00
abstract::Diabetic foot ulcer treatment currently focuses on targeting bacterial biofilms, while dismissing fungi. To investigate this, we used an in vitro biofilm model containing bacteria and fungi, reflective of the wound environment, to test the impact of antimicrobials. Here we showed that while monotreatment approaches in...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00672-17
更新日期:2017-08-24 00:00:00
abstract::Tilorone hydrochloride characteristically induces an unusually delayed and prolonged interferon response not commonly associated with other synthetic inducers. Maximum circulating interferon levels of 8,000 to 10,000 units/ml were detected 12 hr postinoculation and persisted for up to 30 hr after administration of til...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.2.2.73
更新日期:1972-08-01 00:00:00
abstract::The in vitro activity of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] was inhibited by CuCl2 with a 50% inhibitory concentration (IC50) of 2.8 μM. The growth of an amikacin-resistant Klebsiella pneumoniae strain isolated from a neonate with meningitis was inhibited when amikacin was supplemented by t...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01106-15
更新日期:2015-09-01 00:00:00
abstract::Although information about the efficacy and safety experience with caspofungin at 50 mg/m(2) daily is available for children and adolescents, the dosing regimen in infants and toddlers 3 to 24 months of age has yet to be established. We studied the pharmacokinetics and safety of caspofungin at 50 mg/m(2) once daily in...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1128/AAC.01027-08
更新日期:2009-04-01 00:00:00
abstract::This study analyzed the enzymatic basis and molecular epidemiology of amoxicillin-clavulanate-resistant Escherichia coli isolated by the microbiology laboratory of a United States tertiary care hospital. From October 1998 to December 1999, all E. coli isolates were screened for ampicillin-sulbactam resistance. Of 283 ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.48.5.1520-1525.2004
更新日期:2004-05-01 00:00:00
abstract::A clinical isolate of Pseudomonas aeruginosa, PAe191, was found to be highly resistant to all anti-Pseudomonas beta-lactam antibiotics (except imipenem) and resistant also to aminoglycosides. It produced a beta-lactamase (with an apparent pI of 7.6) which was not inhibited by clavulanic acid. Cloning and characterizat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.42.12.3113
更新日期:1998-12-01 00:00:00
abstract::Cilofungin has potent in vitro activity against Candida albicans, but previous in vivo models using twice daily intermittent dosing regimens have not consistently demonstrated in vivo efficacy. Because of the pharmacokinetics of cilofungin in rabbits, it has been suggested that administration by continuous intravenous...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.1.56
更新日期:1992-01-01 00:00:00
abstract::Mycobacterium leprae synthesizes large quantities of a specific phthiocerol-containing phenolic glycolipid in vivo. We have shown earlier that viable M. leprae readily incorporates radiolabeled palmitic acid into phenolic glycolipid I when residing in cultured macrophages in vitro and that this process is inhibited by...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.5.657
更新日期:1989-05-01 00:00:00
abstract::Carbapenemase-producing Gram-negative bacteria (CP-GNB) have increasingly spread worldwide, and different families of carbapenemases have been identified in various bacterial species. Here, we report the identification of five VIM metallo-β-lactamase-producing Alcaligenes faecalis isolates associated with a small outb...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01499-17
更新日期:2017-10-24 00:00:00
abstract::The effect of protein binding on the activity of teicoplanin against Staphylococcus aureus was evaluated. Bactericidal rates of teicoplanin in cation-supplemented Mueller-Hinton broth (SMHB) and in a 1:1 mixture of pooled human serum and cation-supplemented Mueller-Hinton broth (PHS-SMHB) were compared with those of v...
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.35.6.1089
更新日期:1991-06-01 00:00:00
abstract::This study sought to characterize the impact of 3 types of variation on the Standardized Antimicrobial Administration Ratio (SAAR) utilizing local National Healthcare Safety Network (NHSN) data. SAAR and antimicrobial days per 1,000 days present (AD/1000DP) were compiled monthly for Northwestern Memorial Hospital from...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01780-18
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abstract::Enterococcus faecium has emerged as a major opportunistic pathogen for 2 decades with the spread of hospital-adapted multidrug-resistant clones. As members of the intestinal microbiota, they are subjected to numerous bacterial stresses, including antibiotics at subinhibitory concentrations (SICs). Since fluoroquinolon...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02763-16
更新日期:2017-04-24 00:00:00
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
更新日期:2014-08-01 00:00:00
abstract::Clofazimine (CFZ) is a poorly soluble antibiotic and anti-inflammatory drug indicated for the treatment of leprosy. In spite of its therapeutic value, CFZ therapy is accompanied by the formation of drug biocrystals that accumulate within resident tissue macrophages, without obvious toxicological manifestations. Theref...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00265-16
更新日期:2016-05-23 00:00:00
abstract::The nucleoside analogues acyclovir (ACV) and famciclovir (FCV) reduce the frequency and severity of herpes simplex virus 2 (HSV-2) genital shedding, yet despite their high potency in vitro and a lack of induced drug resistance, frequent episodes of breakthrough mucosal shedding occur. We tested a published stochastic,...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01114-13
更新日期:2013-12-01 00:00:00
abstract::Bacterial adaptation to external stresses and toxic compounds is a key step in the emergence of multidrug-resistant strains that are a serious threat to human health. Although some of the proteins and regulators involved in antibiotic resistance mechanisms have been described, no information is available to date conce...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01481-06
更新日期:2007-09-01 00:00:00
abstract::In this study, our objective was to determine whether a synergistic antimicrobial combination in vitro would be beneficial in the downregulation of pneumococcal virulence genes and whether the associated inflammation of the lung tissue induced by multidrug-resistant Streptococcus pneumoniae infection in vivo needs to ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.03245-14
更新日期:2014-09-01 00:00:00
abstract::Many risk factors associated with aminoglycoside nephrotoxicity have been identified in humans and experimental animals. They include an initial high rate of creatinine clearance, high initial peak levels in serum, age, sex, duration of therapy, liver disease, and renal infection. The concomitant administration of ste...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.32.7.992
更新日期:1988-07-01 00:00:00
abstract::MprF is responsible for the lysinylation of phosphatidylglycerol (PG) to synthesize the positively charged phospholipid (PL) species, lysyl-PG (L-PG). It has been proposed that the single-nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) are associated with a gain-in-function phenotype in terms ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00970-15
更新日期:2015-08-01 00:00:00
abstract::A series of 3,5-dioxopyrazolidines was identified as novel inhibitors of UDP-N-acetylenolpyruvylglucosamine reductase (MurB). Compounds 1 to 3, which are 1,2-bis(4-chlorophenyl)-3,5-dioxopyrazolidine-4-carboxamides, inhibited Escherichia coli MurB, Staphyloccocus aureus MurB, and E. coli MurA with 50% inhibitory conce...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.50.2.556-564.2006
更新日期:2006-02-01 00:00:00
abstract::There are no data comparing outcomes of patients treated with ceftazidime-avibactam versus comparators for carbapenem-resistant Enterobacteriaceae infections. At our center, ceftazidime-avibactam treatment of carbapenem-resistant Klebsiella pneumoniae bacteremia was associated with higher rates of clinical success (P ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00883-17
更新日期:2017-07-25 00:00:00
abstract::Previous studies have shown that the proton pump inhibitor omeprazole has antimalarial activity in vitro. The interactions of omeprazole with commonly used antimalarial drugs were assessed in vitro. Omeprazole and quinine combinations were synergistic; however, chloroquine and omeprazole combinations were antagonistic...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.5.1304
更新日期:1999-05-01 00:00:00
abstract::Berberine, a quaternary alkaloid, and several of its derivatives were tested for efficacy against Leishmania donovani and Leishmania braziliensis panamensis in golden hamsters. Tetrahydroberberine was less toxic and more potent than berberine against L. donovani but was not as potent as meglumine antimonate (Glucantim...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.34.5.918
更新日期:1990-05-01 00:00:00