Rapid visualized assessment of drug efficacy in live mice with a selectable marker-free autoluminescent Klebsiella pneumoniae

Tian, Xirong; Gao, Yurui; Wang, Shuai; Hameed, H. M. Adnan; Yu, Wei; Fang, Cuiting; Zhang, Jingran; Tan, Yi; Cao, Zhen; Guan, Ping; Hu, Jinxing; Liu, Jianxiong; Zhong, Nanshan; Zhang, Tianyu

doi:10.1016/j.bios.2020.112919

Cited by 6 publications

(6 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our approach involved a stable chromosomal insertion of the luxCDABE operon and made use of the ribosomal rplU promoter to facilitate constitutive gene expression from viable bacteria. We have demonstrated that bioluminescence can provide a direct measurement of viable K. pneumoniae in broth grown bacteria, as has been similarly demonstrated in a recent study using a Tn7 transposon insertion strategy to generate a bioluminescent clinical isolate of K. pneumoniae [62]. However, unlike this previous study, we have further demonstrated that the bioluminescence of K. pneumoniae continues to facilitate correlation between viable bacterial number and lux in host tissues.…”

Section: Discussionsupporting

confidence: 72%

See 1 more Smart Citation

Direct monitoring of meropenem therapeutic efficacy against Klebsiella pneumoniae respiratory infection by bioluminescence imaging

Fodah

Scott

Warawa

2023

Journal of Medical Microbiology

View full text Add to dashboard Cite

Introduction. Klebsiella pneumoniae is a major threat to public health worldwide. It is the causative agent for multiple disease presentations including urinary tract infection, septicemia, liver abscess, wound infection and respiratory tract infection. K. pneumoniae causes community- and hospital-acquired pneumonia, which is a devastating disease associated with high mortality rates. Hypothesis. There is a growing concern about the emergence of multidrug-resistant K. pneumoniae strains complicating the treatment with the current available therapeutics; therefore, there is an urgent need for the development of new antimicrobial agents. Aim. K. pneumoniae causes an acute respiratory disease in mice and in the current work we investigated the capability to perform non-invasive monitoring of bioluminescent Klebsiella to monitor therapeutic efficacy. Methodology. We engineered a bioluminescence reporter strain of K. pneumoniae to monitor the impact of antibiotics in a murine respiratory disease model. Results. We demonstrate that bioluminescence correlates with bacterial numbers in host tissues allowing for a non-invasive enumeration of bacterial replication in vivo. Light production is directly linked to bacterial viability, and this novel bioluminescent K. pneumoniae strain enabled monitoring of the efficacy of meropenem therapy in arresting bacterial proliferation in the lung. Conclusion. The use of non-invasive bioluminescent imaging improves preclinical animal model testing to detect study outcome earlier and with higher sensitivity.

show abstract

Section: Discussionsupporting

confidence: 72%

“…pneumoniae in broth grown bacteria, as has been similarly demonstrated in a recent study using a Tn7 transposon insertion strategy to generate a bioluminescent clinical isolate of K. pneumoniae [62]. However, unlike this previous study, we have further demonstrated that the bioluminescence of K.…”

Section: Discussionsupporting

confidence: 63%

Direct monitoring of meropenem therapeutic efficacy against Klebsiella pneumoniae respiratory infection by bioluminescence imaging

Fodah

Scott

Warawa

2023

Journal of Medical Microbiology

View full text Add to dashboard Cite

show abstract

“…These results demonstrated an impressive sensitivity of bacteria bioluminescence for the detection of oxygen with a K m of 12 μM. Because the bioluminescence of bacteria luciferase system does not require the addition of external substrates, successful expression of luciferase system (lux gene) have been achieved in prokaryotic cells, 27,47 mammal cells, 28,48 and plant cells. 49 Major challenge at the present stage was the relatively weak bioluminescence intensity.…”

Section: Resultsmentioning

confidence: 87%

Imaging the oxygen wave with a single bioluminescent bacterium

Wang

et al. 2021

Chem. Sci.

View full text Add to dashboard Cite

show abstract

“…The MIC was defined as the lowest concentration, resulting in clarity in turbidity relative to that of untreated control cultures 50,51 .…”

Section: Mics To Non-mycobacteria Determinationmentioning

confidence: 99%

Ilamycin E and ilamycin F are dual inhibitors of ClpX and ClpC1 in mycobacteria

Gao,

Fang,

Zhou

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Combatting drug-resistantMycobacterium tuberculosis(Mtb) necessitates the discovery of novel anti-Mtb agents targeting unexploited molecular pathways. The Clp protease system, integral to protein homeostasis in Mtb, has emerged as a promising target. We report that ilamycins exhibit potent antimycobacterial activity by specifically targeting ClpX and ClpC1. Spontaneous resistance to ilamycin E (ILE) and ilamycin F (ILF) in Mtb mutants correlated with mutations in ClpC1 and ClpX. Molecular docking simulations suggest these mutations occur at critical residues in the N-terminal domain (NTD) of MtbClpC1 and MtbClpX. Functional analyses, including gene over-expression inMycobacterium marinumand targeted gene editing inMycobacterium abscessus(Mab) andMycobacterium smegmatis(Msm), substantiated the significance of these mutations in conferring ILE and ILF resistance. Gene silencing heightened the susceptibility of recombinant Mab and Msm strains to ILE and ILF, concurrently impairing their growth. Differential scanning fluorimetry confirmed the stabilization of MtbClpC1-NTD by ILE and ILF. Moreover, ILE markedly impeded the proteolytic function of the ClpC1P1P2 complex without diminishing ClpC1 ATPase activity. Collectively, our findings demonstrate that ilamycins exert mycobactericidal effects by disrupting ClpC1 and ClpX functions, leading to proteostasis dysregulation. This study underscores the therapeutic potential of targeting the Clp protease system in the treatment of tuberculosis.

show abstract

Rapid visualized assessment of drug efficacy in live mice with a selectable marker-free autoluminescent Klebsiella pneumoniae

Cited by 6 publications

References 33 publications

Direct monitoring of meropenem therapeutic efficacy against Klebsiella pneumoniae respiratory infection by bioluminescence imaging

Direct monitoring of meropenem therapeutic efficacy against Klebsiella pneumoniae respiratory infection by bioluminescence imaging

Imaging the oxygen wave with a single bioluminescent bacterium

Ilamycin E and ilamycin F are dual inhibitors of ClpX and ClpC1 in mycobacteria

Contact Info

Product

Resources

About