Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model

Gregory T. Robertson; Victoria A. Ektnitphong; Michael S. Scherman; Matthew B. McNeil; Devon Dennison; Aaron Korkegian; Anthony J. Smith; Jason Halladay; David S. Carter; Yi Xia; Yasheen Zhou; Wai Choi; Pamela W. Berry; Weimin Mao; Vincent Hernandez; M. R.K. Alley; Tanya Parish; Anne J. Lenaerts

doi:10.1128/AAC.02071-18

Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model

Gregory T. Robertson
, Victoria A. Ektnitphong
, Michael S. Scherman
, Matthew B. McNeil
, Devon Dennison
, Aaron Korkegian
, Anthony J. Smith
, Jason Halladay
, David S. Carter
, Yi Xia
, Yasheen Zhou
, Wai Choi
, Pamela W. Berry
, Weimin Mao
, Vincent Hernandez
, M. R.K. Alley
, Tanya Parish
, Anne J. Lenaerts

Colorado State University
Infectious Disease Research Institute
Pfizer
TB Discovery Research

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

Abstract

AN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis. In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid. AN12855 drug levels were better retained in necrotic lesions and caseum where the majority of hard to treat, extracellular bacilli reside. Owing to these combined attributes, AN12855 represents a promising alternative to the frontline an-tituberculosis agent isoniazid.

Original language	English
Article number	e02071-18
Journal	Antimicrobial Agents and Chemotherapy
Volume	63
Issue number	4
DOIs	https://doi.org/10.1128/AAC.02071-18
Publication status	Published - 11 Feb 2019
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Antimicrobial resistance
C3HeB/FeJ mice
Caseum
Drug development
Isoniazid
Necrotic lesions
Tuberculosis

Access to Document

10.1128/AAC.02071-18

Cite this

Robertson, G. T., Ektnitphong, V. A., Scherman, M. S., McNeil, M. B., Dennison, D., Korkegian, A., Smith, A. J., Halladay, J., Carter, D. S., Xia, Y., Zhou, Y., Choi, W., Berry, P. W., Mao, W., Hernandez, V., Alley, M. R. K., Parish, T., & Lenaerts, A. J. (2019). Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model. Antimicrobial Agents and Chemotherapy, 63(4), Article e02071-18. https://doi.org/10.1128/AAC.02071-18

@article{184d4307686b4724954f7eede74926ea,

title = "Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model",

abstract = "AN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis. In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid. AN12855 drug levels were better retained in necrotic lesions and caseum where the majority of hard to treat, extracellular bacilli reside. Owing to these combined attributes, AN12855 represents a promising alternative to the frontline an-tituberculosis agent isoniazid.",

keywords = "Antimicrobial resistance, C3HeB/FeJ mice, Caseum, Drug development, Isoniazid, Necrotic lesions, Tuberculosis",

author = "Robertson, \{Gregory T.\} and Ektnitphong, \{Victoria A.\} and Scherman, \{Michael S.\} and McNeil, \{Matthew B.\} and Devon Dennison and Aaron Korkegian and Smith, \{Anthony J.\} and Jason Halladay and Carter, \{David S.\} and Yi Xia and Yasheen Zhou and Wai Choi and Berry, \{Pamela W.\} and Weimin Mao and Vincent Hernandez and Alley, \{M. R.K.\} and Tanya Parish and Lenaerts, \{Anne J.\}",

year = "2019",

month = feb,

day = "11",

doi = "10.1128/AAC.02071-18",

language = "English",

volume = "63",

journal = "Antimicrobial Agents and Chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

number = "4",

}

Robertson, GT, Ektnitphong, VA, Scherman, MS, McNeil, MB, Dennison, D, Korkegian, A, Smith, AJ, Halladay, J, Carter, DS, Xia, Y, Zhou, Y, Choi, W, Berry, PW, Mao, W, Hernandez, V, Alley, MRK, Parish, T & Lenaerts, AJ 2019, 'Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model', Antimicrobial Agents and Chemotherapy, vol. 63, no. 4, e02071-18. https://doi.org/10.1128/AAC.02071-18

Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model. / Robertson, Gregory T.; Ektnitphong, Victoria A.; Scherman, Michael S. et al.
In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 4, e02071-18, 11.02.2019.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model

AU - Robertson, Gregory T.

AU - Ektnitphong, Victoria A.

AU - Scherman, Michael S.

AU - McNeil, Matthew B.

AU - Dennison, Devon

AU - Korkegian, Aaron

AU - Smith, Anthony J.

AU - Halladay, Jason

AU - Carter, David S.

AU - Xia, Yi

AU - Zhou, Yasheen

AU - Choi, Wai

AU - Berry, Pamela W.

AU - Mao, Weimin

AU - Hernandez, Vincent

AU - Alley, M. R.K.

AU - Parish, Tanya

AU - Lenaerts, Anne J.

PY - 2019/2/11

Y1 - 2019/2/11

N2 - AN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis. In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid. AN12855 drug levels were better retained in necrotic lesions and caseum where the majority of hard to treat, extracellular bacilli reside. Owing to these combined attributes, AN12855 represents a promising alternative to the frontline an-tituberculosis agent isoniazid.

AB - AN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis. In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid. AN12855 drug levels were better retained in necrotic lesions and caseum where the majority of hard to treat, extracellular bacilli reside. Owing to these combined attributes, AN12855 represents a promising alternative to the frontline an-tituberculosis agent isoniazid.

KW - Antimicrobial resistance

KW - C3HeB/FeJ mice

KW - Caseum

KW - Drug development

KW - Isoniazid

KW - Necrotic lesions

KW - Tuberculosis

U2 - 10.1128/AAC.02071-18

DO - 10.1128/AAC.02071-18

M3 - Article

C2 - 30745397

AN - SCOPUS:85063669096

SN - 0066-4804

VL - 63

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 4

M1 - e02071-18

ER -

Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model

Abstract

UN SDGs

Keywords

Access to Document

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