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Investigating Mycobacterium tuberculosis L,D‐transpeptidases as novel drug targets
Author(s) -
Basta Leighanne,
Pan Ying,
Kaushik Amit,
Lloyd Evan,
Townsend Craig,
Staker Bart,
Lukacs Christine,
Bianchet Mario,
Lamichhane Gyanu
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.613.6
Subject(s) - mycobacterium tuberculosis , peptidoglycan , tuberculosis , enzyme , computational biology , biology , microbiology and biotechnology , antibiotics , bacteria , biochemistry , genetics , medicine , pathology
The final step of peptidoglycan (PG) biosynthesis in bacteria involves cross‐linking of peptide side chains. This step in Mycobacterium tuberculosis is catalyzed by L,D‐ and D,D‐transpeptidases that generate 3→3 and 4→3 transpeptide linkages, respectively. M. tuberculosis PG is predominantly 3→3 cross‐linked, and Ldt Mt2 is the dominant L,D‐transpeptidase. There are four additional sequence paralogs of Ldt Mt2 encoded by the genome of this pathogen, and the reason for this apparent redundancy is unknown. Here, we present microbiological, biochemical, and structural data suggesting paralogs Ldt Mt2 , Ldt Mt3 , and Ldt Mt5 are not functionally redundant. Further, we demonstrate that at least two of these paralogs are acylated by carbapenem antibiotics. Importantly, the work presented here provides structural evidence of acylation of Ldt Mt2 by tebipenem, an orally available carbapenem, and biapenem. We have generated strains of M. tuberculosis that lack functional copies of Ldt Mt2 , Ldt Mt3 , or Ldt Mt5 , and these strains are more susceptible to killing by select carbapenems, osmotic shock, and/or chemical probes. Additionally, the different strains display unique phenotypes when cultured under different conditions, further suggesting these enzymes serve non‐redundant roles in maintaining the physiology of the M. tuberculosis cell wall. Taken together, the results from our studies highlight the essentiality of L,D‐transpeptidases in proper cell wall maintenance. Further investigation into the physiological roles of these enzymes is warranted, as these enzymes represent unexploited drug targets. Support or Funding Information NIH Grants R21AI111739 and DP2OD008459 to GL.