Conjugation to Enterobactin and Salmochelin S4 Enhances
the Antimicrobial Activity and Selectivity of β‑Lactam
Antibiotics against Nontyphoidal Salmonella
posted on 2021-03-10, 23:03authored byArtur Sargun, Martina Sassone-Corsi, Tengfei Zheng, Manuela Raffatellu, Elizabeth M. Nolan
The
pathogen Salmonella enterica is a leading
cause of infection worldwide. Nontyphoidal Salmonella (NTS) serovars typically cause inflammatory diarrhea in healthy
individuals, and can cause bacteremia in immunocompromised patients,
children, and the elderly. Management of NTS infection poses a challenge
because antibiotic treatment prolongs fecal shedding of the pathogen
and is thus not recommended for most patients. In recent years, the
emergence of antibiotic resistance in NTS has also become a major
issue. Thus, new therapeutic strategies to target NTS are needed.
Here, we evaluated whether six siderophore-β-lactam conjugates
based on enterobactin (Ent) and salmochelin S4 (digulcosylated Ent,
DGE) provide antimicrobial activity against the two highly prevalent
NTS serovars Typhimurium and Enteritidis by targeting the siderophore
receptors FepA and/or IroN. The conjugates showed 10- to 1000-fold
lower minimum inhibitory concentrations against both serovars Typhimurium
and Enteritidis compared to the parent antibiotics under iron limitation
and were recognized and transported by FepA and/or IroN. NTS treated
with the Ent/DGE-β-lactam conjugates exhibited aberrant cellular
morphologies suggesting inhibition of penicillin-binding proteins,
and the conjugates selectively killed NTS in coculture with Staphylococcus aureus. Lastly, the DGE-based conjugates
proved to be effective at inhibiting growth of NTS in the presence
of the Ent-sequestering protein lipocalin-2. This work describes the
successful use of siderophore-antibiotic conjugates against NTS and
highlights the opportunity for narrowing the activity spectrum of
antibiotics by using Ent and DGE to target enteric bacterial pathogens.