Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella

Abstract

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-βlactam 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.

Anti-inflammatory Effect of Probiotic Limosilactobacillus reuteri KUB-AC5 Against Salmonella Infection in a Mouse Colitis Model

“…MDR Salmonella strains are currently spreading in the human food supply chain and have a huge impact on economics and health ( Tasmin et al, 2019 ; Castro-Vargas et al, 2020 ; Chen et al, 2020 ). This concern raised the alarm on the need to find alternative ways to control this important foodborne pathogen ( Kongsanan et al, 2020 ; Mao et al, 2021 ; Sargun et al, 2021 ).…”

Probiotic Characteristics and Anti-inflammatory Properties of an Indian Indigenous Lactobacillus plantarum against Pathogenic Salmonella Typhimurium

“…Salmonella Typhimurium (ST) is a gram negative enteric pathogen 43 which enters human gut through consumption of contaminated food or drink. An increase in antibiotic resistance strains of ST raised the concern and developed the need to find alternative prophylactic and therapeutic agents to control this important gastrointestinal pathogen [44][45][46] . S.…”

Advances in the Synthesis of Enterobactin, Artificial Analogues, and Enterobactin-Derived Antimicrobial Drug Conjugates and Imaging Tools for Infection Diagnosis

“…Scheme 13 Synthesis of enterobactin-and salmochelin -lactam-conjugates based on enterobactin derivatives 164 and 164′ by Nolan and co-workers 68,195,202,204 (antimicrobial payloads highlighted in red). This document was downloaded for personal use only.…”

“…Nevertheless, looking at the so far unmatched general success of the basic enterobactin derivative developed by Nolan and co-workers, 68,195,[201][202][203][204]219 it is not surprising that the general concept of an attachment point via a carboxylate in the 5-position of the catechol unit is the object of further studies for the construction of enterobactin-derived carrier molecules.…”