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Next generation antibiotic combinations to combat pan-drug resistant Klebsiella pneumoniae.
Kaur, Jan Naseer; Singh, Navaldeep; Smith, Nicholas M; Klem, Jack F; Cha, Raymond; Lang, Yinzhi; Chen, Liang; Kreiswirth, Barry; Holden, Patricia N; Bulitta, Jürgen B; Tsuji, Brian T.
Afiliação
  • Kaur JN; Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, NY, USA. jannasee@buffalo.edu.
  • Singh N; Division of Clinical and Translational Therapeutics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA. jannasee@buffalo.edu.
  • Smith NM; Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, NY, USA.
  • Klem JF; Division of Clinical and Translational Therapeutics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
  • Cha R; Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, NY, USA.
  • Lang Y; Division of Clinical and Translational Therapeutics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
  • Chen L; Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, NY, USA.
  • Kreiswirth B; Division of Clinical and Translational Therapeutics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
  • Holden PN; Center for Infectious Diseases Next Generation Therapeutics, University at Buffalo, Buffalo, NY, USA.
  • Bulitta JB; Division of Clinical and Translational Therapeutics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
  • Tsuji BT; Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, FL, USA.
Sci Rep ; 14(1): 3148, 2024 02 07.
Article em En | MEDLINE | ID: mdl-38326428
ABSTRACT
Antimicrobial resistance has emerged as one of the leading public health threats of the twenty-first century. Gram-negative pathogens have been a major contributor to the declining efficacy of antibiotics through both acquired resistance and tolerance. In this study, a pan-drug resistant (PDR), NDM-1 and CTX-M-15 co-producing isolate of K. pneumoniae, CDC Nevada, (Kp Nevada) was exposed to the clinical combination of aztreonam + ceftazidime/avibactam (ATM/CAZ/AVI) to overcome metallo-ß-lactamases. Unexpectedly, the ß-lactam combination resulted in long filamentous cell formation induced by PBP3 inhibition over 168 h in the hollow fiber infection model experiments with eventual reversion of the total population upon drug removal. However, the addition of imipenem to the two drug ß-lactam combination was highly synergistic with suppression of all drug resistant subpopulations over 5 days. Scanning electron microscopy and fluorescence microscopy for all imipenem combinations in time kill studies suggested a role for imipenem in suppression of long filamentous persisters, via the formation of metabolically active spheroplasts. To complement the imaging studies, salient transcriptomic changes were quantified using RT-PCR and novel cassette assay evaluated ß-lactam permeability. This showed significant upregulation of both spheroplast protein Y (SPY), a periplasmic chaperone protein that has been shown to be related to spheroplast formation, and penicillin binding proteins (PBP1, PBP2, PBP3) for all combinations involving imipenem. However, with aztreonam alone, pbp1, pbp3 and spy remained unchanged while pbp2 levels were downregulated by > 25%. Imipenem displayed 207-fold higher permeability as compared with aztreonam (mean permeability coefficient of 17,200 nm/s). Although the clinical combination of aztreonam/avibactam and ceftazidime has been proposed as an important treatment of MBL Gram-negatives, we report the first occurrence of long filamentous persister formation. To our knowledge, this is the first study that defines novel ß-lactam combinations involving imipenem via maximal suppression of filamentous persisters to combat PDR CDC Nevada K. pneumoniae.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ceftazidima / Compostos Azabicíclicos / Klebsiella pneumoniae Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ceftazidima / Compostos Azabicíclicos / Klebsiella pneumoniae Idioma: En Ano de publicação: 2024 Tipo de documento: Article