Bacterial cell division proteins as antibiotic targets

Blaauwen, Tanneke den; Andreu, José Manuel; Monasterio, Octavio

doi:10.1016/j.bioorg.2014.03.007

Cited by 76 publications

(70 citation statements)

References 201 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As of this review, there are no documented natural FtsZ-inhibiting antibiotics, however other small-molecule antimicrobials are being investigated for FtsZ inhibition [82]. These molecules exclusively inhibit FtsZ and subsequent formation of the bacterial cell wall.…”

Section: A Novel Target: Septum Formation Utilised By Garvicin a And mentioning

confidence: 98%

Bacteriocins and their position in the next wave of conventional antibiotics

Cavera

Arthur

Kashtanov

et al. 2015

International Journal of Antimicrobial Agents

161

View full text Add to dashboard Cite

Section: A Novel Target: Septum Formation Utilised By Garvicin a And mentioning

confidence: 98%

Bacteriocins and their position in the next wave of conventional antibiotics

Cavera

Arthur

Kashtanov

et al. 2015

International Journal of Antimicrobial Agents

161

View full text Add to dashboard Cite

“…The emergence of multi-drug-resistant gonococci in the community and the potential future losses of effective antibiotics against GC (65) should turn our focus to the development of antimicrobials that attack this pathogen in new ways. The approach of disrupting division or cell separation has shown promise, with several division inhibitors targeting FtsZ entering preclinical evaluation (66). In the gonococcus, the non-redundant, seemingly non-essential enzymes that are important in cell separation (like AmiC or LtgC) should be considered as antimicrobial targets.…”

Section: Discussionmentioning

confidence: 99%

Amidase Activity of AmiC Controls Cell Separation and Stem Peptide Release and Is Enhanced by NlpD in Neisseria gonorrhoeae

Lenz

Stohl

Robertson

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The human-restricted pathogen Neisseria gonorrhoeae encodes a single N-acetylmuramyl-L-alanine amidase involved in cell separation (AmiC), as compared with three largely redundant cell separation amidases found in Escherichia coli (AmiA, AmiB, and AmiC). Deletion of amiC from N. gonorrhoeae results in severely impaired cell separation and altered peptidoglycan (PG) fragment release, but little else is known about how AmiC functions in gonococci. Here, we demonstrated that gonococcal AmiC can act on macromolecular PG to liberate cross-linked and non-cross-linked peptides indicative of amidase activity, and we provided the first evidence that a cell separation amidase can utilize a small synthetic PG fragment as substrate (GlcNAc-MurNAc(pentapeptide)-GlcNAc-MurNAc (pentapeptide)). An investigation of two residues in the active site of AmiC revealed that Glu-229 is critical for both normal cell separation and the release of PG fragments by gonococci during growth. In contrast, Gln-316 has an autoinhibitory role, and its mutation to lysine resulted in an AmiC with increased enzymatic activity on macromolecular PG and on the synthetic PG derivative. Curiously, the same Q316K mutation that increased AmiC activity also resulted in cell separation and PG fragment release defects, indicating that activation state is not the only factor determining normal AmiC activity. In addition to displaying high basal activity on PG, gonococcal AmiC can utilize metal ions other than the zinc cofactor typically used by cell separation amidases, potentially protecting its ability to function in zinc-limiting environments. Thus gonococcal AmiC has distinct differences from related enzymes, and these studies revealed parameters for how AmiC functions in cell separation and PG fragment release. Peptidoglycan (PG)2 is a critical structural macromolecule that makes up the cell wall surrounding the cytoplasmic membrane of nearly all bacteria. This cage-like structure is made up of long polysaccharide strands that are composed of repeating units of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) with short peptide stems (3-5 amino acids) covalently attached to the MurNAc moiety (1). Depending on the organism, some proportion of peptide stems are crosslinked to peptides on adjacent strands, whereas others remain non-cross-linked. Cross-linking provides structural integrity for the macromolecule and contributes to the determination of bacterial shape.Neisseria gonorrhoeae (the gonococcus or GC) is a Gramnegative bacterium, obligate human pathogen, and etiologic agent of the sexually transmitted infection gonorrhea. Gonorrhea is the second most common reportable bacterial infection in the United States with an estimated 820,000 cases annually (2). A robust inflammatory response is the cause of much of the damage observed during GC infection and is triggered by the release of lipo-oligosaccharide, porin proteins, and fragments of PG (3-5). In particular, N. gonorrhoeae release a greater abundance of PG fragments than Escherichia co...

show abstract

“…27–30 Other small molecule 25 FtsZ assembly modulators include nucleotide analogs 31–33 and nucleotide replacing inhibitors, 34–36 among many compounds reported to interact with FtsZ. 37–39 …”

Section: Introductionmentioning

confidence: 99%