Advances in Bacterial Methionine Aminopeptidase Inhibition

Abstract

Methionine aminopeptidases (MetAPs) are metalloenzymes that cleave the N-terminal methionine from newly synthesized peptides and proteins. These MetAP enzymes are present in bacteria, and knockout experiments have shown that MetAP activity is essential for cell life, suggesting that MetAPs are good antibacterial drug targets. MetAP enzymes are also present in the human host and selectivity is essential. There have been significant structural biology efforts and over 65 protein crystal structures of bacterial MetAPs are deposited into the PDB. This review highlights the available crystallographic data for bacterial MetAPs. Structural comparison of bacterial MetAPs with human MetAPs highlights differences that can lead to selectivity. In addition, this review includes the chemical diversity of molecules that bind and inhibit the bacterial MetAP enzymes. Analysis of the structural biology and chemical space of known bacterial MetAP inhibitors leads to a greater understanding of this antibacterial target and the likely development of potential antibacterial agents.

Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents

“…16 Species of this general structure only exhibit potent inhibition of MetAPs containing Mn(II) cofactors, with essentially no activity observed for MetAPs possessing Fe(II), Co(II) or Ni(II) metals. 16 Although this class of inhibitors have demonstrated activity against a number of bacterial MetAPs, including Mycobacterium tuberculosis , 18–19 B. pseudomallei , 11 E. coli . 12, 20 and Acinetobacter baumannii , 21 there are currently no reports detailing the selectivity of bacterial versus human MetAPs.…”

“…This result is interesting, as quinolinol species have been demonstrated to inhibit MetAP species utilizing Co(II) cofactors over species utilizing Mn(II) cofactors. 16 The quinolinol compounds were not as selective against Hs MetAP2, with the observed activities being comparable to Rp MetAP1 (Table 5). However, Hs MetAP2 inhibition has been suggested as a treatment for tumor growth abatement (antiangiogenic properties) 30 and a lack of specificity regarding these two targets may not be of striking clinical significance.…”

“…16 It is noteworthy that some compounds based upon the quinolinol scaffold have been identified as pan-assay interference compounds (PAINS) 17 due to both their promiscuous inhibition of metalloenzymes and their ability to form reactive methides. As this is early stage, proof of concept research, this information can useful in the design of next generation compounds that are devoid of such characteristics.…”

“…These compounds have been shown to most effectively inhibit MetAPs utilizing Co(II) or Ni(II) cofactors in vitro , with weaker activity observed for Mn(II) cofactors. 16 Interestingly, MetAP species bearing Fe(II) cofactors exhibit essentially no reduction in enzymatic turnover in the presence of triazole inhibitors.…”

Therapeutic and biotechnological applications of substrate specific microbial aminopeptidases

“…Bacterial methionine aminopeptidases have been implicated as potential targets for developing broad spectrum antibacterial drugs (Helgren et al 2016;Schiffmann et al 2006). Inhibitors of methionine aminopeptidase are having therapeutic function since they are reported to have regulatory roles in angiogenesis and tumor progression (Selvakumar et al 2005;Zhong and Bowen 2006).…”