Effect of A22 on the Conformation of Bacterial Actin MreB

Abstract

The mechanism of the antibiotic molecule A22 is yet to be clearly understood. In a previous study, we carried out molecular dynamics simulations of a monomer of the bacterial actin-like MreB in complex with different nucleotides and A22, and suggested that A22 impedes the release of Pi from the active site of MreB after the hydrolysis of ATP, resulting in filament instability. On the basis of the suggestion that Pi release occurs on a similar timescale to polymerization and that polymerization can occur in the absence of nucleotides, we sought in this study to investigate a hypothesis that A22 impedes the conformational change in MreB that is required for polymerization through molecular dynamics simulations of the MreB protofilament in the apo, ATP+, and ATP-A22+ states. We suggest that A22 inhibits MreB in part by antagonizing the ATP-induced structural changes required for polymerization. Our data give further insight into the polymerization/depolymerization dynamics of MreB and the mechanism of A22.

Status of Targeting MreB for the Development of Antibiotics

“…The same study demonstrated further that the mechanism of A22 partly involves its ability to impede the release of P i from the active site of MreB after ATP hydrolysis, leading to filament instability. A more recent similar study (Awuni and Mu, 2019) showed that A22 inhibits MreB in part by impeding an ATP-induced conformational change that it requires to polymerize into stable double protofilaments. It does appear that the mechanism of A22 is multidimensional and involves several effects on the structure and dynamics of MreB.…”

“…Currently, the nucleotide binding site, the A22 binding pocket, and the inter-protofilament interface of MreB have been identified as potential targets for antibiotics. The nucleotide binding site is an important target for antibiotics development because nucleotide binding plays a crucial role in the structure and dynamics of MreB (Bean and Amann, 2008;Colavin et al, 2014;Van Den Ent et al, 2014;Awuni et al, 2016;Awuni and Mu, 2019). ATP induces the polymerization of MreB into filaments required for cell wall biosynthesis (Van Den Ent et al, 2001;Popp et al, 2010;Awuni and Mu, 2019).…”

“…The nucleotide binding site is an important target for antibiotics development because nucleotide binding plays a crucial role in the structure and dynamics of MreB (Bean and Amann, 2008;Colavin et al, 2014;Van Den Ent et al, 2014;Awuni et al, 2016;Awuni and Mu, 2019). ATP induces the polymerization of MreB into filaments required for cell wall biosynthesis (Van Den Ent et al, 2001;Popp et al, 2010;Awuni and Mu, 2019). Interestingly, the polymerization of MreB induces ATP hydrolysis, which serves as a timing process to coordinate depolymerization (Esue et al, 2005;Bean and Amann, 2008;Popp et al, 2010;Gunning et al, 2015).…”

Phylogenetic origin and sequence features of MreB from the wall-less swimming bacteria Spiroplasma

“…Next, to investigate the SMreB sequences corresponding to the sequences conserved in walled bacteria [15,16,17,29,30], we predicted the ancestral sequences and 3D structures for SMreBs 1-5, HMreB, BMreBH, and BMreB ( Fig. 2C-E, S2, Data set 3).…”

“…walled-bacterial MreB move toward an adjacent MreB molecule to interact with each other [16], these amino acid substitutions of SMreBs, especially SMreBs 2 and 4, may affect the flexibility and interaction strength, allowing them to show polymerization characters different to those of walled-bacterial MreBs (Fig. 2F).…”