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Janice Carr/CDC
The quest to understand a prolonged infection in an infant with acute myeloid leukemia (AML) has led to the discovery of a mutation that allows bacteria to tolerate antibiotic therapy.
Researchers described this discovery in the journal mBio.
“These findings detail a ‘perfect storm’ for development of antibiotic tolerance by bacteria that already pose a clinical challenge,” said study author Jason Rosch, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“The same conditions may be present in other patients with immune systems that have been compromised by chemotherapy or disease,” added co-author Joshua Wolf, MBBS, also of St. Jude.
The “perfect storm” involved a patient who was 6 weeks old when she was diagnosed with AML. The treatment wiped out her white blood cells, and, despite infection-control measures, she developed a bloodstream infection with vancomycin-resistant Enterococcus faecium (VRE).
The infection persisted for 26 days and only resolved after her immune system recovered. She then successfully completed AML treatment.
In-depth DNA sequencing of 22 VRE samples collected during the patient’s infection helped researchers link the prolonged infection to a point mutation in the relA gene of VRE.
The 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, and this likely primed the bacteria to survive exposure to multiple antibiotics, the researchers said.
The team also noted that relA-mutant VRE was susceptible to the antibiotics linezolid and daptomycin in minimum inhibitory concentration testing and during planktonic growth.
However, when growing in biofilm, relA-mutant VRE could tolerate high doses of both antibiotics.
“This mutation has particular clinical significance because the antibiotics involved, linezolid and daptomycin, are the last line of defense against VRE infection,” Dr Wolf said.
Among the compounds in development for the treatment of bacterial biofilms is the experimental antibiotic ADEP-4. In this study, ADEP-4 killed relA-mutant and non-mutant VRE growing in biofilm in the lab.
“In the future, compounds like ADEP-4 may provide a new approach to resolving persistent infections,” Dr Wolf said.
Dr Rosch noted that evidence gleaned from tracking the evolution of VRE throughout the infection suggested the patient’s immune-compromised state was essential to survival of the mutant VRE.
Gene transcription was altered significantly in relA-mutant VRE and produced biofilms that were less robust and possibly unlikely to otherwise survive.
“The case expands our understanding of the role of the stringent response in susceptibility and tolerance to a wide range of antibiotics, especially in biofilms,” Dr Rosch said. “It also demonstrates that these mutations can develop and gain a foothold during a human infection.”
