Yersinia pestis, the causative agent of plague, is arguably the most devastating pathogen in human history. Paleogenomic studies indicate its presence as early as the Neolithic era. It evolved from Yersinia pseudotuberculosis, with divergence estimates ranging from 1500 to 20,000 years ago, most often placed around 5000 years ago. Its natural reservoirs are wild mammals, particularly rodents, with fleas serving as vectors, while humans are incidental hosts. Over time, Y. pestis has acquired multiple virulence factors that disrupt immune responses and can lead to rapid, often fatal disease. Because the bacterium is maintained in wildlife cycles and can spill over to domestic animals, eradication is difficult, if not impossible. Nevertheless, mitigation is achievable using a One Health approach integrating human health, animal health, and the health of the environment. Neither vaccines nor monoclonal antibodies are currently licensed in most Western countries, thus, antibiotics remain the mainstay of therapy. Timely administration, ideally within 24 h of symptom onset, is critical, particularly in pneumonic forms. Phage therapy is under investigation as a potential treatment. Though often neglected in high-income settings, plague remains endemic in several regions, with the highest burden reported in Madagascar and the Democratic Republic of the Congo.

Botulinum neurotoxins are synthetized by anaerobic, spore-forming bacteria that inhibit acetylcholine release at the level of the neuromuscular and autonomic cholinergic junctions, thus inducing a series of symptoms, the most relevant of which is flaccid paralysis. At least seven serotypes and over 40 subtypes are known, and they are among the most poisonous natural substances. There are different forms of botulism according to the route of contamination, but the clinical manifestation of descending symmetric flaccid paralysis is consistent, regardless of the route of contamination. It is very severe and potentially lethal. The induced paralysis lasts as long as the toxin is active, with variable length, according to the serotype of the toxin. This transient activity, as well as the precise mechanism of action, are the basis for the rationale behind use of the toxin in therapy for several clinical conditions, particularly, spastic conditions, as well as chronic migraine and axillary hyperhidrosis. The toxin has also been approved for the reduction in facial wrinkles; all these clinical applications, coupled with the toxin’s risks, have earned botulinum the title of a two-faced Janus protein. No approved vaccines are currently available, andthe only approved antidotes are the human specific intravenous immunoglobulins for infant botulism and the heptavalent equine immunoglobulins/(F(ab’)² for adults. Nanobodies, which show great promise, may penetrate neuronal cells to inactivate the toxin within the cytoplasm, and Ebselen, a non-toxic, economic, small-molecule inhibitor, has the characteristic of inhibiting the toxin irrespective of the serotype.

Tularemia is a plague-like, potentially fatal zoonosis caused by the coccobacillus Francisella tularensis. It was discovered at the beginning of the last century in the United States and was soon recognized in Japan and in the former Soviet Union as the cause of clinical conditions that had been known for one and two centuries, respectively. More than 250 animal species are susceptible to infection, with rodents and lagomorphs serving as key reservoirs, and several vectors may transmit the disease, mainly ticks and mosquitoes. Humans are incidental hosts and are infected primarily by two F. tularensis subspecies, tularensis and holarctica: the former is more severe and is found almost exclusively in North America, whereas the latter is distributed throughout the Northern Hemisphere, mainly in Europe and Asia. Tularemia is highly infectious; therefore, diagnostic cultures should be handled in biosafety level 3 laboratories. Nevertheless, interhuman transmission is exceedingly rare. Although tularemia is relatively uncommon, it shows a re-emerging pattern at the global level, particularly in Europe. As with plague, mitigation may be more effectively achieved through a One Health approach. Neither approved vaccines nor therapeutic antibodies are currently available, whereas aminoglycoside, tetracycline, and quinolone antibiotics are effective. Owing to its high infectivity, its ease of transmission by inhalation, its clinical severity, with a prolonged and debilitating course, and its potential lethality, F. tularensis has long been considered a potential biological weapon, particularly if antibiotic-resistant strains were used. Although natural antibiotic resistance has not been described to date, research programs aimed at obtaining resistant strains have been conducted. It has been suggested that the disease was already present in the Middle East during the second millennium BC; should this hypothesis be confirmed by paleogenomic studies, plague and tularemia would have coexisted for more than three millennia, with plague masking the less severe tularemia. Many challenges related to tularemia are still unresolved.