Research on a patient with acute myeloid leukemia has revealed new information on how bacteria mutate to survive antibiotics.
Almost as fast as bacteria gain new methods of resistance to antibiotics, researchers are uncovering more information on these new methods in an attempt to thwart the attempts. By studying a long-term infection in an infant who is being treated for leukemia, researchers at St. Jude’s Children’s Research Hospital have learned more about how bacteria survive antibiotic therapy.
The patient, an infant at St. Jude’s, was being treated for acute myeloid leukemia, “a type of cancer in which the bone marrow makes too many immature lymphocytes (a type of white blood cell).” Treatment for the cancer, “wiped out [the patient’s] white blood cells, which help protect against infection, and despite infection-control measures, she developed a blood stream infection with vancomycin-resistant Enterococcus faecium (VRE),” according to a press release on the recent findings. This infection continued to persist in the patient for 28 days and did not clear until after her immune system had recovered. According to Jason Rosch, PhD, assistant member of the St. Jude Department of Infectious Diseases, and corresponding author on the study, the immunocompromised state of the patient created a “perfect storm for the development of antibiotic tolerance by bacteria that already pose a clinical challenge.”
The researchers collected VRE samples during the patient’s infection and performed DNA sequencing on 22 of the samples. The testing revealed a point mutation in the relA gene of VRE. This mutation, “inappropriately activated the stringent response pathway, which bacteria use to survive under stress and to tolerate antibiotics. The mutation resulted in elevated levels of the signaling molecule alarmone. The increased alarmone likely primed the bacteria to survive exposure to multiple antibiotics,” according to the researchers.
"This mutation has particular clinical significance because the antibiotics involved, linezolid and daptomycin, are the last line of defense against VRE infection," said Joshua Wolf, MBBS, assistant member of the St. Jude Department of Infectious Diseases and co-corresponding author.
The mutated bacteria were likely able to persist due to their growth in biofilms, which tend to develop on catheters, heart valves, and other surfaces in the body. According to the press release, “Biofilms feature dormant cells called persister cells that are shielded from the immune system and are tough to eradicate with available antibiotics.” More research on these persister cells has shown that they are able to lay the bacteria in a dormant state, hibernating until the “deadly” antibiotic treatment is complete and they can thrive once again.
Additional research has shown that an experimental antibiotic, ADEP-4, has been effective at “activating an enzyme to kill persister cells and eradicate bacterial biofilm.” According to the researchers in the St. Jude study, “ADEP-4 killed relA-mutant and non-mutant VRE growing in biofilm in the laboratory.” This antibiotic may prove to be effective in fighting persistent infections that thrive in biofilms in the future, according to the authors.