Scientists have discovered a new antibiotic derived from AstraZeneca drugs that can remove bacteria potentially causing sepsis and pneumonia in mice without harming beneficial bacteria. As reported in a paper published in Nature by scientists from the University of Illinois Urbana-Champaign, indicates that such drugs could bypass major drawbacks of some current antibiotics, which cause severe side effects.
The researchers selected lolamicin—an antibiotic that killed all pathological bacteria in cell cultures and mice, but spared helpful gram-negative bacteria usually found in the mice’s gastrointestinal tracts. The study’s principal investigator, Paul Hergenrother, Ph.D., expected the new antibiotic to target only pathogenic bacteria and spare the beneficial ones.
Lolamicin inhibits the activity of the Lol system—a transport system specific to gram-negative bacteria involved in the translocation of lipoproteins within the bacterium. This antibiotic emerged from a primary screen of compounds initially discovered by AstraZeneca, though it was not used in the original study. Moreover, the compounds’ action was even more toxic toward gram-negative bacteria if their defense mechanisms were pre-dismantled. Using strains that preferred pathogenic bacteria over beneficial gut bacteria, they identified the best candidates as reservoirs of new antibiotics that selectively kill gram-negative pathogens without compromising beneficial bacteria.
Lolamicin was developed through modifications and experimentation. The data showed that, in high concentrations, lolamicin wiped out 90% of E. coli, K. pneumoniae, and E. cloacae obtained from patient samples without negatively impacting gram-positive or beneficial gut gram-negative bacteria. Furthermore, it did not exhibit any cytotoxicity against mammalian cell lines or red blood cells.
Further experiments in a mouse model of sepsis and pneumonia due to MDR E. coli, K. pneumoniae, or E. cloacae yielded promising outcomes. Mice with sepsis treated with lolamicin all survived, while 70 percent of the mice with pneumonia also survived. Most mice treated with the control solution or a comparative compound died within 48 hours.
The team also investigated whether lolamicin’s effect on sparing beneficial bacteria in cell studies would be reflected in animal studies. Mice were administered lolamicin, amoxicillin, and clindamycin at therapeutic concentrations for three consecutive days, after which fecal samples were collected for the subsequent month. Amoxicillin and clindamycin adversely affected the proportion of beneficial gut microbes; however, lolamicin had less impact on bacterial populations.
The researchers also examined the impact of lolamicin on eradicating C. difficile, a pathogen that can occur as a secondary infection after certain antibiotics. The hypothesis that lolamicin would not hinder the clearance of C. difficile was confirmed: mice treated with lolamicin had a low level of C. difficile colonization compared to mice treated with amoxicillin or clindamycin, which had high levels of C. difficile colonization.
