From solo to duet, intersections of natural product assembly with self-resistance

Abstract

It has become a ‘received wisdom’ that there are universal links between natural product (NP) self-resistance and biosynthesis, which needs interpretation. This review highlights evidence of intersection between NP self-resistance and biosynthesis.

LexR Positively Regulates the LexABC Efflux Pump Involved in Self-Resistance to the Antimicrobial Di- N -Oxide Phenazine in Lysobacter antibioticus

“…Studies on self-resistance genes against antibiotics have enabled the discovery of novel natural products with resistance genes as selective markers. These genes have enabled the investigation of strategies to deal with increasing bacterial antibiotic resistance ( 27 – 29 ). Antibiotic efflux via molecular pumps are an effective resistance mechanism.…”

On the evolution of natural product biosynthesis

“…There are however, a number of common themes within these BGCs that facilitate biosynthesis of such a diverse range of chemical entities. In general the genes for the scaffold of the NP are present within the BGC, the enzymes for tailoring their biosynthesis, genes that encode one or more transcription factors (TFs) to regulate biosynthesis, genes that facilitate transport of the NP following biosynthesis and an immunity mechanism (Bibb, 2005;Blin et al, 2021;Medema and Fischbach, 2015;Navarro-Muñoz et al, 2019;Terlouw et al, 2022;Wu et al, 2022).…”

“…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).…”

“…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). It is also being observed with increasing regularity that resistance to antimicrobial NPs can be achieved through duplication of the cellular target in producers to provide resistance, and often not colocated with the BGC (Alanjary et al, 2017;Kale et al, 2011;Tang et al, 2015).…”

Antifungal Macrolides Kongjuemycins from Coral-Associated Rare Actinomycete Pseudonocardia kongjuensis SCSIO 11457

“…The long acyl side chains are often engineered to alter the chain length in searching for bioactivity-improved compounds . In some cases, the long acyl side chain is applied as a self-resistance strategy by being decorated as a cryptic protecting group that is removed extracellularly to activate the drug, such as xenocoumacin, saframycins, and safracins . Interestingly, different long acyl chains are found in 2 – 4 , probably derived from different starter units, but it remains unclear whether they originate from a secondary PKS pathway or from the primary fatty acid biosynthesis.…”