The first antibiotic, salvarsan, was deployed in 1910. In just over 100 years antibiotics have drastically changed modern medicine and extended the average human lifespan by 23 years. The discovery of penicillin in 1928 started the golden age of natural product antibiotic discovery that peaked in the mid-1950s. Since then, a gradual decline in antibiotic discovery and development and the evolution of drug resistance in many human pathogens has led to the current antimicrobial resistance crisis. Here we give an overview of the history of antibiotic discovery, the major classes of antibiotics and where they come from. We argue that the future of antibiotic discovery looks bright as new technologies such as genome mining and editing are deployed to discover new natural products with diverse bioactivities. We also report on the current state of antibiotic development, with 45 drugs currently going through the clinical trials pipeline, including several new classes with novel modes of action that are in phase 3 clinical trials. Overall, there are promising signs for antibiotic discovery, but changes in financial models are required to translate scientific advances into clinically approved antibiotics.

We report a new Streptomyces species named S. formicae that was isolated from the African fungus-growing plant-ant Tetraponera penzigi and show that it produces novel pentacyclic polyketides that are active against MRSA and VRE. The chemical scaffold of these compounds, which we have called the formicamycins, is similar to the fasamycins identified from the heterologous expression of clones isolated from environmental DNA, but has significant differences that allow the scaffold to be decorated with up to four halogen atoms. We report the structures and bioactivities of 16 new molecules and show, using CRISPR/Cas9 genome editing, that biosynthesis of these compounds is encoded by a single type 2 polyketide synthase biosynthetic gene cluster in the S. formicae genome. Our work has identified the first antibiotic from the Tetraponera system and highlights the benefits of exploring unusual ecological niches for new actinomycete strains and novel natural products.

β-Lactone natural products occur infrequently in nature but possess a variety of potent and valuable biological activities. They are commonly derived from β-hydroxy-α-amino acids, which are themselves valuable chiral building blocks for chemical synthesis and precursors to numerous important medicines. However, despite a number of excellent synthetic methods for their asymmetric synthesis, few effective enzymatic tools exist for their preparation. Here we report cloning of the biosynthetic gene cluster for the β-lactone antibiotic obafluorin and delineate its biosynthetic pathway. We identify a nonribosomal peptide synthetase with an unusual domain architecture and an L-threonine:4-nitrophenylacetaldehyde transaldolase responsible for (2S,3R)-2-amino-3-hydroxy-4-(4-nitrophenyl)butanoate biosynthesis. Phylogenetic analysis sheds light on the evolutionary origin of this rare enzyme family and identifies further gene clusters encoding L-threonine transaldolases. We also present preliminary data suggesting that L-threonine transaldolases might be useful for the preparation of L-threo-β-hydroxy-α-amino acids.

We must reduce reliance on agrochemicals, and there is increasing interest in using bacterial strains to promote plant growth and protect against disease. Our study follows up reports thatArabidopsis thalianaspecifically recruitsStreptomycesbacteria to its roots. We test the hypotheses that they offer benefits to theirA. thalianahosts and that strains isolated from these plants might be used as probiotics. We isolatedStreptomycesstrains fromA. thalianaroots and genome sequenced five phylogenetically distinct strains. Genome mining and bioassays indicated that all five have plant growth-promoting properties, including production of indole-3-acetic acid (IAA), siderophores, and aminocyclopropane-1-carboxylate (ACC) deaminase. Three strains significantly increasedA. thalianagrowthin vitroand in combination in soil. Another produces potent filipin-like antifungals and protected germinating wheat seeds against the fungal pathogenGaeumannomyces graminisvar.tritici(wheat take-all fungus). We conclude that introducingStreptomycesstrains into the root microbiome provides significant benefits to plants.

Acromyrmex leafcutter ants form a mutually beneficial symbiosis with the fungus Leucoagaricus gongylophorus and with Pseudonocardia bacteria. Both are vertically transmitted and actively maintained by the ants. The fungus garden is manured with freshly cut leaves and provides the sole food for the ant larvae, while Pseudonocardia cultures are reared on the ant-cuticle and make antifungal metabolites to help protect the cultivar against disease. If left unchecked, specialized parasitic Escovopsis fungi can overrun the fungus garden and lead to colony collapse. We report that Escovopsis upregulates the production of two specialized metabolites when it infects the cultivar. These compounds inhibit Pseudonocardia and one, shearinine D, also reduces worker behavioral defenses and is ultimately lethal when it accumulates in ant tissues. Our results are consistent with an active evolutionary arms race between Pseudonocardia and Escovopsis, which modifies both bacterial and behavioral defenses such that colony collapse is unavoidable once Escovopsis infections escalate.

Erythromycin, avermectin and rapamycin are clinically useful polyketide natural products produced on modular polyketide synthase multienzymes by an assembly-line process in which each module of enzymes in turn specifies attachment of a particular chemical unit. Although polyketide synthase encoding genes have been successfully engineered to produce novel analogues, the process can be relatively slow, inefficient, and frequently low-yielding. We now describe a method for rapidly recombining polyketide synthase gene clusters to replace, add or remove modules that, with high frequency, generates diverse and highly productive assembly lines. The method is exemplified in the rapamycin biosynthetic gene cluster where, in a single experiment, multiple strains were isolated producing new members of a rapamycin-related family of polyketides. The process mimics, but significantly accelerates, a plausible mechanism of natural evolution for modular polyketide synthases. Detailed sequence analysis of the recombinant genes provides unique insight into the design principles for constructing useful synthetic assembly-line multienzymes.