Interplay of emerging and established technologies drives innovation in natural product antibiotic discovery

Abstract

A continued rise of antibiotic resistance and shortages of effective antibiotics necessitate the discovery and development of new antibiotics with novel modes of action (MoAs) against resistant pathogens. While natural products remain the best resource for antibiotic discovery, their exploration faces many challenges, including (i) unknown MoAs, (ii) high rediscovery rates, (iii) tedious isolation and structure elucidation, and (iv) insufficient production for further development. We have identified recent innovations in screening methods, microbiology, bioinformatics, and metabolomics technologies, as well as natural product-inspired synthesis and synthetic biology, that have contributed to new natural product antibiotics in the past two years. We highlight their interplay as the key element for successful applications, driving future opportunities to increase the pool of natural product-based antibacterial antibiotics.

Figure 1. Workflows applied for the discovery of new antibiotics in the past two years. Different molecules are color and dots marks the respective key method that was chosen as starting point. CRF = Chlororesistoflavin

A roadmap to NP antibiotic discovery: Selected examples of new antibiotics highlighting the interplay between the different methods (grey squares) discussed. Shape size correlates to the method usage, dots mark the respective key method that was chosen as the starting point for each study, and arrows can be followed to the final product (colored hexagons) ●→⬢. Grey: Malacidin (2018, Fig 3) [10]; light blue: Clipibicyclene (2022, Fig 3) [11]; dark blue: Chlororesistoflavine (2022, Fig 3) [12]; red: Macolacin (2022, Fig 4) [13]; yellow: Iboxamycin (2021, Fig 4) [14]; rose: MBA3 (2021, Fig 3) [15]; orange: Corbomycin (2020, Fig 3) [16]; turquoise: Amycobactin (2020, Fig 3) [17]; black: Cilagicin (2022, Fig 4) [18]; light green: syCPA 63 (2022, Fig 4) [19]; light purple: Dynobactin (2022, Fig 2) [20]; brown: Dynaplanin (2022, Fig 3) [21]; dark green: Harundomycin (2022, Fig 3) [22]; purple: Evybactin (2022, Fig 2) [23].

Figure 2

Eukaryotic symbionts were prioritized for identification of unprecedented NPs with a desirable ratio between antibacterial activity and cytotoxicity, resulting in the discovery of evybactin [23] and dynobactin A [20]. Both NPs address promising new antibiotic targets.

Figure 3

Novel NPs with evolution and integration of emerging and established technologies as key element: Amycobactin [17], dynaplanin [21], and chlororesistoflavines [12] were discovered in microbiology-center approaches, that also involved genomics, phenotypic screening, target identification and MoA. The discoveries of malacidins [10], MBA3 [15], clipibicyclene [11], and corbomycin [16] involved various combinations of the described methods, while always having genomics as center piece. Harundomycin [22] was discovered combining metabolomics with microbiology and genomics, which ultimately also led to a target assignment.

Figure 4

NPs with desired biological activities have inspired the discovery of the four analogues with improved activities: macolacin [13], cilagicin [18], syCPA 63 [19], and iboxymycin [14]. Notably, genomics, target identification, and MoA were the key methods serving as a rational to develop their chemical structures.