Biosynthesis of Aurodox, a Type III Secretion System Inhibitor from Streptomyces goldiniensis

Abstract

Enterohemorrhagic Escherichia coli (EHEC) is a significant global pathogen for which traditional antibiotic treatment is not recommended. Aurodox inhibits the ability of EHEC to establish infection in the host gut through the specific targeting of the type III secretion system while circumventing the induction of toxin production associated with traditional antibiotics.

Targeting bacterial pathogenesis by inhibiting virulence-associated Type III and Type IV secretion systems

“…Another T3SS inhibitor isolated from Streptomyces is the kirromycin derivative aurodox ( Kimura et al., 2011 ). This linear polyketide compound is highly similar to kirromycin, from which it differs only in the methylation of its pyridone moiety ( McHugh et al., 2022 ). Aurodox was first identified in a screen for inhibitors of T3SS-mediated hemolysis in EPEC and was subsequently shown to decrease the secretion of effector proteins EspB, EspF, and Map without affecting bacterial growth.…”

On the evolution of natural product biosynthesis

“…The schematic (Fig. 2) shows the organization of a canonical BGC, where the scaffold generating enzymes (in this case (McHugh et al, 2022), a series of large megasynthases encoding polyketide synthases [PKS] and non-ribosomal peptide synthases [NRPS]). The tailoring enzymes are clustered and consist of a range of enzyme families and within these are co-located the regulatory genes and the resistance and transport mechanism.…”

“…Contained within BGCs are genes that have been acquired from primary metabolism which has led to a number of hypotheses around how these can give rise to novel activities through expansion (duplication or Horizontal Gene Transfer [HGT]) and recruitment to the cluster, where enzymes have relaxed constraints of delivering their primary metabolic function may evolve novel substrate specificities and/or activities (Booth et al, 2022;. Remarkably, in many BGCs recruited genes may still resemble their primary metabolic counterparts (e.g aspartate decarboxylates (McHugh et al, 2022;Weber et al, 2008) Resistance mechanisms encoded within BGCs are increasingly under scrutiny in terms of how essential they are for the formation of a BGC (Wu et al, 2022). While conventional thought that export/resistance function is required within the BGC (Liu et al, 2016;Martín et al, 2005;Severi and Thomas, 2019), however there are increasing examples of biosynthesis and self-resistance overlapping (Cui et al, 2020(Cui et al, , 2018Wencewicz, 2019;Wu et al, 2022).…”

“…Architecture of a natural product producing biosynthetic gene cluster. This is the BGC for the biosynthesis of aurodox, a hybrid PKS/NRPS antibiotic from Streptomyces goldiniensis (McHugh et al, 2022). Many NP BGCs have conserved features.…”

Discovery of Efrotomycin Congeners and Heterologous Expression-Based Insights into the Self-Resistance Mechanism

“…The elfamycin family of antibiotics are inhibitors of bacterial protein synthesis by interaction with elongation factor Tu and also show a narrow antibacterial spectrum against human pathogens and excellent growth-promoting activity in animals . The biosynthetic gene clusters (BGCs) have been identified for kirromycin, factumycin, and aurodox; however, the biosynthetic machinery governing the glycosylated elfamycins is not yet clear.…”