Exposure of Pseudomonas aeruginosa to aminoglycosides frequently selects for recalcitrant subpopulations exhibiting an unstable, "adaptive" resistance to these antibiotics. In this study, we investigated the implication in the phenomenon of MexXY-OprM, an active efflux system known to export aminoglycosides in P. aeruginosa. Immunoblotting experiments demonstrated that the transporter MexY, but not the outer membrane pore OprM, was overproduced during the post-drug exposure adaptation period in wild-type strain PAO1. Furthermore, MexY production was dependent upon the degree of bacterial exposure to gentamicin (drug concentration). In contrast to parental strain PAO1, mutants defective in MexXY or in OprM were unable to develop adaptive resistance. Altogether, these results indicate that the resistance process requires the rapid production of MexXY and the interaction of these proteins with the constitutively produced component OprM.
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http://dx.doi.org/10.1128/AAC.47.4.1371-1375.2003 | DOI Listing |
N Engl J Med
January 2025
From Médecins Sans Frontières (L.G., F.V.), Sorbonne Université, INSERM Unité 1135, Centre d'Immunologie et des Maladies Infectieuses (L.G.), Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Sorbonne Université, Hôpital Pitié-Salpêtrière, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (L.G.), and Epicentre (M.G., E. Baudin), Paris, and Translational Research on HIV and Endemic and Emerging Infectious Diseases, Montpellier Université de Montpellier, Montpellier, Institut de Recherche pour le Développement, Montpellier, INSERM, Montpellier (M.B.) - all in France; Interactive Development and Research, Singapore (U.K.); McGill University, Epidemiology, Biostatistics, and Occupational Health, Montreal (U.K.); UCSF Center for Tuberculosis (G.E.V., P.N., P.P.J.P.) and the Division of HIV, Infectious Diseases, and Global Medicine (G.E.V.), University of California at San Francisco, San Francisco; the National Scientific Center of Phthisiopulmonology (A.A., E. Berikova) and the Center of Phthisiopulmonology of Almaty Health Department (A.K.), Almaty, and the City Center of Phthisiopulmonology, Astana (Z.D.) - all in Kazakhstan; Médecins Sans Frontières (C.B., I.M.), the Medical Research Council Clinical Trials Unit at University College London (I.M.), and St. George's University of London Institute for Infection and Immunity (S.W.) - all in London; MedStar Health Research Institute, Washington, DC (M.C.); Médecins Sans Frontières, Mumbai (V. Chavan), the Indian Council of Medical Research Headquarters-New Delhi, New Delhi (S. Panda), and the Indian Council of Medical Research-National AIDS Research Institute, Pune (S. Patil) - all in India; the Centre for Infectious Disease Epidemiology and Research (V. Cox) and the Department of Medicine (H. McIlleron), University of Cape Town, and the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (S.W.) - both in Cape Town, South Africa; the Institute of Tropical Medicine, Antwerp, Belgium (B. C. J.); Médecins Sans Frontières, Geneva (G.F., N.L.); Médecins Sans Frontières, Yerevan, Armenia (O.K.); the National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia (N.K.); Partners In Health (M.K.) and Jhpiego Lesotho (L.O.) - both in Maseru; Socios En Salud Sucursal Peru (L.L., S.M.-T., J.R., E.S.-G., D.E.V.-V.), Hospital Nacional Sergio E. Bernales, Centro de Investigacion en Enfermedades Neumologicas (E.S.-G.), Hospital Nacional Dos de Mayo (E.T.), Universidad Nacional Mayor de San Marcos (E.T.), and Hospital Nacional Hipólito Unanue (D.E.V.-V.) - all in Lima; Global Health and Social Medicine, Harvard Medical School (L.L., K.J.S., M.L.R., C.D.M.), Partners In Health (L.L., K.J.S., M.L.R., C.D.M.), the Division of Global Health Equity, Brigham and Women's Hospital (K.J.S., M.L.R., C.D.M.), the Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, (L.T.), and Harvard T.H. Chan School of Public Health (L.T.) - all in Boston; and the Indus Hospital and Health Network, Karachi, Pakistan (H. Mushtaque, N.S.).
Background: For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis.
Methods: We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z).
Proc Natl Acad Sci U S A
February 2025
Molecular Genetics, Institute of Biology, Faculty of Life Sciences, Humboldt Universität zu Berlin, Berlin 10115, Germany.
The chloroplast genome encodes key components of the photosynthetic light reaction machinery as well as the large subunit of the enzyme central for carbon fixation, Ribulose-1,5-bisphosphat-carboxylase/-oxygenase (RuBisCo). Its expression is predominantly regulated posttranscriptionally, with nuclear-encoded RNA-binding proteins (RBPs) playing a key role. Mutants of chloroplast gene expression factors often exhibit impaired chloroplast biogenesis, especially in cold conditions.
View Article and Find Full Text PDFDrug Deliv Transl Res
January 2025
Kinimmune, Inc. St. Louis, 63141, Missouri, USA.
PD-L1/PD-1 checkpoint inhibitors (CPIs) are mainstream agents for cancer immunotherapy, but the prognosis is unsatisfactory in solid tumor patients lacking preexisting T-cell reactivity. Adjunct therapy strategies including the intratumoral administration of immunostimulants aim to address this limitation. CpG oligodeoxynucleotides (ODNs), TLR9 agonists that can potentiate adaptive immunity, have been widely investigated to tackle PD-L1/PD-1 resistance, but clinical success has been hindered by inconsistent efficacy and immune-related toxicities caused by systemic exposure.
View Article and Find Full Text PDFmBio
January 2025
Department of Microbiology, Genetics, & Immunology, Michigan State University, East Lansing, Michigan, USA.
The emergence and global spread of carbapenem-resistant complex species present a pressing public health challenge. Carbapenem-resistant spp. cause a wide variety of infections, including septic shock fatalities in newborns and immunocompromised adults.
View Article and Find Full Text PDFJ Microbiol Biol Educ
January 2025
Department of Microbiology, University of Georgia, Athens, Georgia, USA.
We present a laboratory module that uses isolation of antibiotic-resistant bacteria from locally collected stream water samples to introduce undergraduate students to basic microbiological culture-based and molecular techniques. This module also educates them on the global public health threat of antibiotic-resistant organisms. Through eight laboratory sessions, students are involved in quality testing of water sources from their neighborhoods, followed by isolation of extended-spectrum beta-lactamase-producing .
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