Slt, MltD, and MltG of Pseudomonas aeruginosa as Targets of Bulgecin A in Potentiation of β-Lactam Antibiotics

David A. Dik, Chinedu S. Madukoma, Shusuke Tomoshige, Choonkeun Kim, Elena Lastochkin, William C. Boggess, Jed F. Fisher, Joshua D. Shrout, Shahriar Mobashery

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5 Citations (Scopus)

Abstract

The interplay between the activities of lytic transglycosylases (LTs) and penicillin-binding proteins (PBPs) is critical for the health of the bacterial cell wall. Bulgecin A (a natural-product inhibitor of LTs) potentiates the activity of β-lactam antibiotics (inhibitors of PBPs), underscoring this intimate mechanistic interdependence. Bulgecin A in the presence of an appropriate β-lactam causes bulge deformation due to the formation of aberrant peptidoglycan at the division site of the bacterium. As Pseudomonas aeruginosa, a nefarious human pathogen, has 11 LT paralogs, the answer as to which LT activity correlates with β-lactam potentiation is important and is currently unknown. Growth of P. aeruginosa PAO1 strains harboring individual transposon-insertion mutants at each of the 11 genes for LTs, in the presence of the β-lactam antibiotic ceftazidime or meropenem, implicated the gene products of slt, mltD, and mltG (of the 11), in bulge formation and potentiation. Hence, the respective enzymes would be the targets of inhibition by bulgecin A, which was indeed documented. We further demonstrated by imaging in real time and by SEM that cell lysis occurs by the structural failure of this bulge. Upon removal of the β-lactam antibiotic prior to lysis, P. aeruginosa experiences delayed recovery from the elongation and bulge phenotype in the presence of bulgecin A. These observations argue for a collaborative role for the target LTs in the repair of the aberrant cell wall, the absence of activities of which in the presence of bulgecin A results in potentiation of the β-lactam antibiotic.

Original languageEnglish
JournalACS Chemical Biology
DOIs
Publication statusAccepted/In press - 2019 Jan 1
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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    Dik, D. A., Madukoma, C. S., Tomoshige, S., Kim, C., Lastochkin, E., Boggess, W. C., Fisher, J. F., Shrout, J. D., & Mobashery, S. (Accepted/In press). Slt, MltD, and MltG of Pseudomonas aeruginosa as Targets of Bulgecin A in Potentiation of β-Lactam Antibiotics. ACS Chemical Biology. https://doi.org/10.1021/acschembio.8b01025