Bruce L Geller1, Lixin Li1, Fabian Martinez1, Erin Sully1, Carolyn R Sturge2, Seth M Daly2, Christine Pybus2, David E Greenberg2,3. 1. Department of Microbiology, 226 Nash Hall, Oregon State University, Corvallis, OR 97331, USA. 2. Department of Internal Medicine, 5323 Harry Hines Blvd., University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 3. Department of Microbiology, 5323 Harry Hines Blvd., University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Abstract
Background: Klebsiella pneumoniae is an opportunistic pathogen and many strains are multidrug resistant. KPC is one of the most problematic resistance mechanisms, as it confers resistance to most β-lactams, including carbapenems. A promising platform technology for treating infections caused by MDR pathogens is the nucleic acid-like synthetic oligomers that silence bacterial gene expression by an antisense mechanism. Objectives: To test a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) in a mouse model of K. pneumoniae infection. Methods: PPMOs were designed to target various essential genes of K. pneumoniae and screened in vitro against a panel of diverse strains. The most potent PPMOs were further tested for their bactericidal effects in broth cultures and in established biofilms. Finally, a PPMO was used to treat mice infected with a KPC-expressing strain. Results: The most potent PPMOs targeted acpP, rpmB and ftsZ and had MIC75s of 0.5, 4 and 4 μM, respectively. AcpP PPMOs were bactericidal at 1-2 × MIC and reduced viable cells and biofilm mass in established biofilms. In a mouse pneumonia model, therapeutic intranasal treatment with ∼30 mg/kg AcpP PPMO improved survival by 89% and reduced bacterial burden in the lung by ∼3 logs. Survival was proportional to the dose of AcpP PPMO. Delaying treatment by 2, 8 or 24 h post-infection improved survival compared with control groups treated with PBS or scrambled sequence (Scr) PPMOs. Conclusions: PPMOs have the potential to be effective therapeutic agents against KPC-expressing, MDR K. pneumoniae.
Background: Klebsiella pneumoniae is an opportunistic pathogen and many strains are multidrug resistant. KPC is one of the most problematic resistance mechanisms, as it confers resistance to most β-lactams, including carbapenems. A promising platform technology for treating infections caused by MDR pathogens is the nucleic acid-like synthetic oligomers that silence bacterial gene expression by an antisense mechanism. Objectives: To test a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) in a mouse model of K. pneumoniae infection. Methods: PPMOs were designed to target various essential genes of K. pneumoniae and screened in vitro against a panel of diverse strains. The most potent PPMOs were further tested for their bactericidal effects in broth cultures and in established biofilms. Finally, a PPMO was used to treat mice infected with a KPC-expressing strain. Results: The most potent PPMOs targeted acpP, rpmB and ftsZ and had MIC75s of 0.5, 4 and 4 μM, respectively. AcpP PPMOs were bactericidal at 1-2 × MIC and reduced viable cells and biofilm mass in established biofilms. In a mousepneumonia model, therapeutic intranasal treatment with ∼30 mg/kg AcpP PPMO improved survival by 89% and reduced bacterial burden in the lung by ∼3 logs. Survival was proportional to the dose of AcpP PPMO. Delaying treatment by 2, 8 or 24 h post-infection improved survival compared with control groups treated with PBS or scrambled sequence (Scr) PPMOs. Conclusions: PPMOs have the potential to be effective therapeutic agents against KPC-expressing, MDR K. pneumoniae.
Authors: Lucas D Tilley; Orion S Hine; Jill A Kellogg; Jed N Hassinger; Dwight D Weller; Patrick L Iversen; Bruce L Geller Journal: Antimicrob Agents Chemother Date: 2006-08 Impact factor: 5.191
Authors: James J Howard; Carolyn R Sturge; Dina A Moustafa; Seth M Daly; Kimberly R Marshall-Batty; Christina F Felder; Danniel Zamora; Marium Yabe-Gill; Maria Labandeira-Rey; Stacey M Bailey; Michael Wong; Joanna B Goldberg; Bruce L Geller; David E Greenberg Journal: Antimicrob Agents Chemother Date: 2017-03-24 Impact factor: 5.191
Authors: Brett L Mellbye; Susan E Puckett; Luke D Tilley; Patrick L Iversen; Bruce L Geller Journal: Antimicrob Agents Chemother Date: 2008-11-17 Impact factor: 5.191
Authors: Lise Goltermann; Niloofar Yavari; Meiqin Zhang; Anubrata Ghosal; Peter E Nielsen Journal: Front Microbiol Date: 2019-05-24 Impact factor: 5.640
Authors: Dina A Moustafa; Ashley W Wu; Danniel Zamora; Seth M Daly; Carolyn R Sturge; Christine Pybus; Bruce L Geller; Joanna B Goldberg; David E Greenberg Journal: mBio Date: 2021-01-12 Impact factor: 7.867
Authors: Rakel Arrazuria; Bernhard Kerscher; Karen E Huber; Jennifer L Hoover; Carina Vingsbo Lundberg; Jon Ulf Hansen; Sylvie Sordello; Stephane Renard; Vincent Aranzana-Climent; Diarmaid Hughes; Philip Gribbon; Lena E Friberg; Isabelle Bekeredjian-Ding Journal: Front Microbiol Date: 2022-09-08 Impact factor: 6.064