7. 6. 2024
The bacterium Bordetella pertussis, the causative agent of whooping cough, has evolved to become so highly adapted to humans that it has lost the ability to synthesize one of the key amino acids, cysteine. A new study by researchers at the Institute of Microbiology of the Czech Academy of Sciences (IMIC CAS) shows that this dependence on the human host is an integral part of the bacterium’s infectious strategy. At the same time, the findings suggest that this dependence could potentially be exploited in the future to develop novel antimicrobial therapies. The study indicates that regulation of sulfur and cysteine metabolism is essential not only for bacterial survival but also for the ability of B. pertussis to cause disease.
Whooping cough is a highly contagious respiratory disease. Although effective vaccines are available, many countries have experienced a resurgence of cases in recent years. A better understanding of the biology of Bordetella pertussis may therefore contribute to the development of new strategies to combat this infection.
A research team led by Branislav Večerek, head of the Laboratory of Post-Transcriptional Control of Gene Expression, focused on how the bacterium manages sulfur, an element essential for the function of all living cells. Sulfur is a component of numerous biological molecules, and the amino acid cysteine plays a central role in its metabolism. Most bacteria are able to synthesize cysteine from sulfate taken up from their environment. However, as the study’s first author, Argha Saha, explains: “During its evolution, B. pertussis lost a large part of the metabolic pathway required to utilize environmental sulfur and therefore has to obtain cysteine from its human host. For bacterial pathogens, this generally provides a physiological advantage because it saves a substantial amount of energy.”
Cysteine dioxygenases are key enzymes in cysteine metabolism
Excess cysteine can disrupt the intracellular chemical balance and promote the formation of reactive oxygen species. The researchers found that B. pertussis efficiently overcomes this challenge through two enzymes known as cysteine dioxygenases. These enzymes degrade excess cysteine, allowing it to be used not only as a source of sulfur but also as an energy source. Bacteria lacking these genes became significantly more sensitive to excess cysteine and exhibited markedly impaired growth.
Reduced toxin secretion leads to lower virulence
Pertussis toxin is one of the major virulence factors responsible for the severe manifestations of whooping cough. The researchers found that a mutant lacking both cysteine dioxygenases still produced pertussis toxin but secreted it much less efficiently into the surrounding environment, resulting in substantially reduced cytotoxicity toward human immune cells.
“The reduced virulence of the genetically modified bacteria was also evident in a mouse model of infection,” says Branislav Večerek, whose laboratory studies the molecular mechanisms underlying B. pertussis pathogenesis. “Our findings suggest that proper regulation of cysteine metabolism is not merely a matter of bacterial nutrition, but is also closely linked to the pathogen’s ability to cause infection.”
Sulfur metabolism – a new direction for antimicrobial therapy?
The study demonstrates that sulfur metabolism is critically important for B. pertussis. Its metabolic dependence on host-derived cysteine may therefore represent a potential therapeutic opportunity. Interfering with cysteine uptake or metabolism could compromise both bacterial survival and infectivity. These findings open an intriguing avenue for future research aimed at developing new antimicrobial therapies.
PUBLICATION: Saha A, Petráčková D, Holubová J, Beles M, Čurnová I, Staněk O, Večerek B. Two cysteine dioxygenase homologs contribute to the fitness and virulence of a human pathogen. Microbiol Spectr. 2026 Aug 19:e0141426. https://doi.org/10.1128/spectrum.01414-26
