Journal Article

Antimicrobial activity of iron-depriving pyoverdines against human opportunistic pathogens

Pérez-Berlanga, Manuela, Kümmerli, Rolf, Vollenweider, Vera, Rehm, Karoline, Bigler, Laurent, Piel, Jörn, Polymenidou, Magdalini, Chepkirui, Clara

2024

Overview

The global rise of antibiotic resistance calls for new drugs against bacterial pathogens. A common approach is to search for natural compounds deployed by microbes to inhibit competitors. Here, we show that the iron-chelating pyoverdines, siderophores produced by environmental Pseudomonas spp., have strong antibacterial properties by inducing iron starvation and growth arrest in pathogens. A screen of 320 natural Pseudomonas isolates used against 12 human pathogens uncovered several pyoverdines with particularly high antibacterial properties and distinct chemical characteristics. The most potent pyoverdine effectively reduced growth of the pathogens Acinetobacter baumannii , Klebsiella pneumoniae, and Staphylococcus aureus in a concentration- and iron-dependent manner. Pyoverdine increased survival of infected Galleria mellonella host larvae and showed low toxicity for the host, mammalian cell lines, and erythrocytes. Furthermore, experimental evolution of pathogens combined with whole-genome sequencing revealed limited resistance evolution compared to an antibiotic. Thus, pyoverdines from environmental strains have the potential to become a new class of sustainable antibacterials against specific human pathogens. Despite the wide range of available antibiotics, a majority work through a similar mechanism, which enables some bacteria to become resistant to medical treatment. This means that the effectiveness of these molecules goes down and many curable infections may no longer be treatable. Collectively, antibiotic resistance poses a similar threat as other major diseases, such as malaria. One promising approach for discovering new antibiotics is to explore natural microbial communities for their ability to produce secondary metabolites with antimicrobial properties. Such metabolites are typically secreted by bacteria to compete with other community members for essential resources including nutrients. A well-known group of secreted metabolites are siderophores, which tightly sequester iron, a critical nutrient for bacterial growth. Each bacterial species produces its own set of specific siderophores, thus leading to a severe competition for iron. Vollenweider et al. investigated whether a group of siderophores secreted by Pseudomonas bacteria, called pyoverdines, are an effective antimicrobial agent against harmful human pathogens. Pyoverdines have a high affinity to iron and prevent competing bacteria from accessing the critical nutrient. This can inhibit their growth by starving them of iron. Vollenweider et al. treated resistant pathogens like Acinetobacter , Klebsiella and Staphylococcus grown in the laboratory, and found that pyoverdines significantly reduce their growth without the bacteria acquiring resistance. To test whether this treatment would work in a living infected animal, the group administered pyoverdines to moth larvae infected with the same pathogens and observed increased survival rates in the host. As iron is also required for human metabolism and found in the haemoglobin of red blood cells, Vollenweider, et al. confirmed pyoverdines do not retrieve iron from haemoglobin. Finally, in laboratory settings, pyoverdines did not negatively affect the growth of a human and a mouse cell line at low concentrations strong enough to inhibit the growth of pathogens. This approach is a promising example of adopting natural mechanisms that can have antimicrobial properties, and siderophores, in particular pyoverdines, may become a useful tool to treat otherwise incurable infections. Further research is needed in living mammalian models to confirm efficacy and safety of this novel antimicrobial treatment.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications, Ltd,eLife Sciences Publications Ltd
• Subject: Acinetobacter baumannii - drug effects / Animals / Anti-Bacterial Agents - pharmacology / antibacterial treatment / Comparative analysis / Control / Evolutionary Biology / Humans / Identification and classification / Iron - metabolism / Klebsiella pneumoniae - drug effects / Larva - drug effects / Larva - microbiology / Microbial Sensitivity Tests / Microbiology and Infectious Disease / Moths - microbiology / Oligopeptides - chemistry / Oligopeptides - metabolism / Oligopeptides - pharmacology / Opportunistic Infections - microbiology / Pathogenic microorganisms / Physiological aspects / Pseudomonas - drug effects / Pseudomonas - genetics / Pseudomonas - metabolism / Pseudomonas spp / pyoverdine / Siderophores (Microbiology) / Staphylococcus aureus - drug effects / Staphylococcus aureus - genetics