Crystal structures of the transpeptidase domain of the Mycobacterium tuberculosis penicillin-binding protein PonA1 reveal potential mechanisms of antibiotic resistance

Filippova, Ekaterina V.; Kieser, Karen J.; Luan, Chi-Hao; Wawrzak, Zdzislaw; Kiryukhina, Olga; Rubin, Eric J.; Anderson, Wayne F.

doi:10.1111/febs.13738

Title: Crystal structures of the transpeptidase domain of the Mycobacterium tuberculosis penicillin-binding protein PonA1 reveal potential mechanisms of antibiotic resistance

Journal Article · 25 May 2016 · Federation of European Biochemical Societies (FEBS) Journal

DOI: https://doi.org/10.1111/febs.13738 · OSTI ID:1254659

Filippova, Ekaterina V. ^[1]; Kieser, Karen J. ^[2]; Luan, Chi-Hao ^[3]; Wawrzak, Zdzislaw ^[4]; Kiryukhina, Olga ^[1]; Rubin, Eric J. ^[5]; Anderson, Wayne F. ^[1]

Northwestern Univ., Evanston, IL (United States). Dept. of Biochemistry and Molecular Genetics; Argonne National Lab. (ANL), Argonne, IL (United States). Bioscience Division. Midwest Center for Structural Genomics (MCSG); Northwestern Univ., Evanston, IL (United States). Feinberg School of Medicine. Center for Structural Genomics of Infectious Diseases (CSGID)
Harvard T.H. School of Public Health, Boston, MA (United States). Dept. of Immunology and Infectious Disease
Argonne National Lab. (ANL), Argonne, IL (United States). Bioscience Division. Midwest Center for Structural Genomics (MCSG); Northwestern Univ., Evanston, IL (United States). High Throughput analysis Lab and Dept. of Molecular Biosciences
Northwestern Univ., Evanston, IL (United States). Synchrotron Research Center. Life Science Collaborative Access Team
Harvard T.H. School of Public Health, Boston, MA (United States). Dept. of Immunology and Infectious Disease; Harvard Medical School, Boston, MA (United States). Dept. of Microbiology and Immunobiology

Mycobacterium tuberculosis is a human respiratory pathogen that causes the deadly disease tuberculosis. The rapid global spread of antibiotic-resistant M. tuberculosis makes tuberculosis infections difficult to treat. To overcome this problem new effective antimicrobial strategies are urgently needed. One promising target for new therapeutic approaches is PonA1, a class A penicillin-binding protein, which is required for maintaining physiological cell wall synthesis and cell shape during growth in mycobacteria. Here, crystal structures of the transpeptidase domain, the enzymatic domain responsible for penicillin binding, of PonA1 from M. tuberculosis in the inhibitor-free form and in complex with penicillin V are reported. We used site-directed mutagenesis, antibiotic profiling experiments, and fluorescence thermal shift assays to measure PonA1’s sensitivity to different classes of β-lactams. Structural comparison of the PonA1 apo-form and the antibiotic-bound form shows that binding of penicillin V induces conformational changes in the position of the loop β4' -a3 surrounding the penicillin-binding site. We have also found that binding of different antibiotics including penicillin V positively impacts protein stability, while other tested β-lactams such as clavulanate or meropenem resulted in destabilization of PonA1. Our antibiotic profiling experiments indicate that the transpeptidase activity of PonA1 in both M. tuberculosis and M. smegmatis mediates tolerance to specific cell wall-targeting antibiotics, particularly to penicillin V and meropenem. Because M. tuberculosis is an important human pathogen, these structural data provide a template to design novel transpeptidase inhibitors to treat tuberculosis infections.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-06CH11357; [085P1000817]; NIH [GM074942]; NSF [DGE1144152; DGE0946799; MCB 1024945; HHS [HHSN272200700058C; HHSN2722012 00026C]

OSTI ID:: 1254659

Alternate ID(s):: OSTI ID: 1254660; OSTI ID: 1625876

Journal Information:: Federation of European Biochemical Societies (FEBS) Journal, Vol. 283, Issue 12; ISSN 1742-464X

Publisher:: Federation of European Biochemical SocietiesCopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 17 works

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