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. 2021 Feb 15:32:115995.
doi: 10.1016/j.bmc.2021.115995. Epub 2021 Jan 7.

Staphylococcus aureus resistance to albocycline can be achieved by mutations that alter cellular NAD/PH pools

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Staphylococcus aureus resistance to albocycline can be achieved by mutations that alter cellular NAD/PH pools

Tyler Scherzi et al. Bioorg Med Chem. .

Abstract

Small molecule target identification is a critical step in modern antibacterial drug discovery, particularly against multi-drug resistant pathogens. Albocycline (ALB) is a macrolactone natural product with potent activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) whose mechanism of action has been elusive to date. Herein, we report biochemical and genomic studies that reveal ALB does not target bacterial peptidoglycan biosynthesis or the ribosome; rather, it appears to modulate NADPH ratios and upregulate redox sensing in the cell consistent with previous studies at Upjohn. Owing to the complexity inherent in biological pathways, further genomic assays are needed to identify the true molecular target(s) of albocycline.

Keywords: Albocycline; Dissociation constants; Mechanism of action; MurA; NADPH; Resistant mutants; Ribosome; Sequencing.

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Conflict of interest statement

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
Albocycline does not inhibit the exit of the peptide chain from the bacterial ribosome: A) Determination of dissociation constant by titrating the [70S] ribosomes (nM) against fixed concentration (5 nM) of BODIPY-erythromycin. B) Determination of % inhibition as a function of solithromycin concentration.
Figure 2.
Figure 2.
Averaged duplicate analysis of S. aureus MurA using increasing concentrations of UDP-GlcNAc. Michaelis-Menten plot was generated using GraphPad Prism.
Figure 3.
Figure 3.
Kinetic analysis and inhibition curves of S. aureus MurA generated using increasing concentrations of albocycline (0μM, 50μM, 100μM, 300μM). As the concentration of ALB increased, the rate of conversion of UDP-GlcNAc to EP-UDP-GlcNAc by MurA also decreased. All Michaelis-Menten curves were generated using GraphPad prism and represent the average of duplicate kinetic reactions for each albocycline concentration.

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