Elsevier

Drug Discovery Today

Volume 6, Issue 18, 15 September 2001, Pages 954-961
Drug Discovery Today

Review
Deformylase as a novel antibacterial target

https://doi.org/10.1016/S1359-6446(01)01925-0Get rights and content

Abstract

Bacterial genomics has revealed a plethora of previously unknown targets of potential use in the discovery of novel antibacterial drugs. However, so far little has emerged from this approach. Peptide deformylase is an interesting target that was discovered more than 30 years ago, but was not exploited until recently. The reawakening of interest in this target resulted from an improved understanding of the enzyme, making it a more tractable and attractive target. Information on the properties of the enzyme, such as its three-dimensional structure, the activity of inhibitors, its resistance and suitability as a target are discussed.

Section snippets

Function of PDF

Protein synthesis is a proven rich source of targets for antibacterial drugs 2. Many of the known antibiotics (e.g. the aminoglycosides, macrolides, tetracyclines and oxazolidinones) work by inhibiting one or more steps of this complex process. Although the protein synthesizing machinery of bacterial and mammalian cells is similar overall, there is enough of a difference to allow for the selective blocking of this process in bacteria. One significant difference is the transformylation and

The essential role of deformylase in bacteria

Currently used antibiotics work by inhibiting the growth of, or killing, bacteria. In the continuing search for new antibiotics that work in this way, it is crucial that any new chosen target is essential for the growth and/or survival of the bacteria. Although alternative approaches to therapy, such as inhibition of virulence, have been attempted, no new drugs have yet emerged from such efforts. The essential nature of deformylase was first suggested in 1994 by two groups 4, 9 working with

Is deformylase present in all bacteria?

The distribution of PDF gene homologs has been studied extensively. Orthologs of deformylase (homolog genes that code for proteins of the same function) are present in all bacterial genomes that have been sequenced completely, and most incomplete genomes have contigs with a PDF homolog (see Fig. 2; 10, 13). The wide distribution of PDF homologs in bacteria suggests that it could provide the basis for discovering broad-spectrum antibacterial drugs. Genomic analysis shows that bacteria have at

The presence and relevance of deformylase in eukaryotes

Several eukaryotic parasites (e.g. Plasmodium falciparum and trypanosomal species) and plants 14 have a PDF gene homolog. Interestingly, the presence of PDF in lower eukaryotes yields potential applications of PDF inhibitors in important diseases, such as malaria or Chaga's disease 14. The presence of PDF activity in humans has been reported in relation to the degradation of formyl-peptides of bacterial origin in the mucosal barrier of the gut 15 but this was apparently only active on

Why has so little progress been made with deformylase until recently?

In the early 1960s, it was established that formylmethionyl-tRNA initiates bacterial protein synthesis 5. However, because few (if any) mature proteins in E. coli retain formylmethionine, it was suspected that a specific enzyme was responsible for removal of the formyl group and PDF activity was first reported by Adams in 1968 (Ref. 18). This study showed that a protein fraction from E. coli was capable of removing the formyl group from the nascent protein. However, subsequent attempts to

Discovering inhibitors of PDF

The discovery of novel antibiotics has been largely an empirical screening process; typically, antibacterial activity is discovered first and the structure of the molecule responsible and the targets involved are established afterwards. Structure- and mechanism-based drug designs represent rational approaches. The fact that PDF is a metalloprotease gives it an added attractiveness as a target for drug discovery. Metalloproteases are among the best studied of enzyme classes 37 and there are

Is antibacterial activity a result of deformylase inhibition?

The fact that a potent PDF inhibitor also inhibits the growth of an intact bacterial cell does not prove that PDF inhibition causes the growth defect. Evidence that the same mechanism of action is involved has come from several lines of research. One of these methods 28 involves the use of the aforementioned E. coli genetic construct in which the sole chromosomal copy of the def gene is under the control of the arabinose-regulated PBAD promoter. In this case, it was shown that the

Resistance to deformylase inhibitors

The frequency and mechanism of resistance to PDF inhibitors have been explored in S. aureus, E. coli, H. influenzae and S. pneumoniae 10, 11, 34, 47. In S. aureus and H. influenzae, spontaneous mutants occur at frequencies of 1 × 10−6 and 1 × 10−8, respectively. In both organisms the mutants harbored changes in the transformylase gene. It was already known that transformylase is not essential in E. coli and can provide a genetic background in which deformylase activity is no longer required for

Activity of deformylase inhibitors in vivo

Although the natural product actinonin is a PDF inhibitor and has in vitro activity against bacteria, it is inactive in vivo 48. The validation of PDF as an in vivo target was provided recently by two synthetic PDF inhibitors VRC3375 (Ref. 27) and BB3497 (Ref. 34) through the curing of staphylococcal septicemia in mice. In both cases, treatments were effective following administration of the PDF inhibitors by the intravenous, subcutaneous or oral routes.

VRC3375 is a potent PDF inhibitor (Ki =

Conclusions and future directions

In choosing an ideal target for the discovery of drugs that directly kill or inhibit the growth of bacteria, there are several important criteria to be considered. Bacterial PDF satisfies the majority of these: it is an essential enzyme, it is present in all clinically relevant bacteria and it is highly conserved. Although PDF has no role in mammalian cytoplasmic-protein synthesis, the recent identification of a human def gene homolog requires further study to better understand the potential

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