In Vitro Antibacterial Activity of Microbial Natural Products against Bacterial Pathogens of Veterinary and Zoonotic Relevance.

Antimicrobial resistance (AMR) is considered one of the greatest threats to both human and animal health. Efforts to address AMR include implementing antimicrobial stewardship programs and introducing alternative treatment options. Nevertheless, effective treatment of infectious diseases caused by bacteria will still require the identification and development of new antimicrobial agents. Eight different natural products were tested for antimicrobial activity against seven pathogenic bacterial species (Brachyspira sp., Chlamydia sp., Clostridioides sp., Mannheimia sp., Mycobacterium sp., Mycoplasma sp., Pasteurella sp.). In a first pre-screening, most compounds (five out of eight) inhibited bacterial growth only at high concentrations, but three natural products (celastramycin A [CA], closthioamide [CT], maduranic acid [MA]) displayed activity at concentrations <2 µg/mL against Pasteurella sp. and two of them (CA and CT) also against Mannheimia sp. Those results were confirmed by testing a larger collection of isolates encompassing 64 Pasteurella and 56 Mannheimia field isolates originating from pigs or cattle, which yielded MIC90 values of 0.5, 0.5, and 2 µg/mL against Pasteurella and 0.5, 4, and >16 µg/mL against Mannheimia for CA, CT, and MA, respectively. CA, CT, and MA exhibited higher MIC50 and MIC90 values against Pasteurella isolates with a known AMR phenotype against commonly used therapeutic antimicrobial agents than against isolates with unknown AMR profiles. This study demonstrates the importance of whole-cell antibacterial screening of natural products to identify promising scaffolds with broad- or narrow-spectrum antimicrobial activity against important Gram-negative veterinary pathogens with zoonotic potential.

Reciprocal Fitness Feedbacks Promote the Evolution of Mutualistic Cooperation.

Mutually beneficial interactions are ubiquitous in nature and have played a pivotal role for the evolution of life on earth. However, the factors facilitating their emergence remain poorly understood. Here, we address this issue both experimentally and by mathematical modeling using cocultures of auxotrophic strains of Escherichia coli, whose growth depends on a reciprocal exchange of amino acids. Coevolving auxotrophic pairs in a spatially heterogeneous environment for less than 150 generations transformed the initial interaction that was merely based on an exchange of metabolic byproducts into a costly metabolic cooperation, in which both partners increased the amounts of metabolites they produced to benefit their corresponding partner. The observed changes were afforded by the formation of multicellular clusters, within which increased cooperative investments were favored by positive fitness feedbacks among interacting genotypes. Under these conditions, non-cooperative individuals were less fit than cooperative mutants. Together, our results highlight the ease with which mutualistic cooperation can evolve, suggesting similar mechanisms likely operate in natural communities. VIDEO ABSTRACT.

Ecology and evolution of metabolic cross-feeding interactions in bacteria.

Literature covered: early 2000s to late 2017Bacteria frequently exchange metabolites with other micro- and macro-organisms. In these often obligate cross-feeding interactions, primary metabolites such as vitamins, amino acids, nucleotides, or growth factors are exchanged. The widespread distribution of this type of metabolic interactions, however, is at odds with evolutionary theory: why should an organism invest costly resources to benefit other individuals rather than using these metabolites to maximize its own fitness? Recent empirical work has shown that bacterial genotypes can significantly benefit from trading metabolites with other bacteria relative to cells not engaging in such interactions. Here, we will provide a comprehensive overview over the ecological factors and evolutionary mechanisms that have been identified to explain the evolution and maintenance of metabolic mutualisms among microorganisms. Furthermore, we will highlight general principles that underlie the adaptive evolution of interconnected microbial metabolic networks as well as the evolutionary consequences that result for cells living in such communities.