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Novel small molecules affecting cell membrane as potential therapeutics for avian pathogenic Escherichia coli.

ABSTRACT: Avian pathogenic Escherichia coli (APEC), a most common bacterial pathogen of poultry, causes multiple extra-intestinal diseases in poultry which results in significant economic losses to the poultry industry worldwide. In addition, APEC are a subgroup of extra-intestinal pathogenic E. coli (ExPEC), and APEC contaminated poultry products are a potential source of foodborne ExPEC infections to humans and transfer of antimicrobial resistant genes. The emergence of multi-drug resistant APEC strains and the limited efficacy of vaccines necessitate novel APEC control approaches. Here, we screened a small molecule (SM) library and identified 11 SMs bactericidal to APEC. The identified SMs were effective against multiple APEC serotypes, biofilm embedded APEC, antimicrobials resistant APECs, and other pathogenic E. coli strains. Microscopy revealed that these SMs affect the APEC cell membrane. Exposure of SMs to APEC revealed no resistance. Most SMs showed low toxicity towards chicken and human cells and reduced the intracellular APEC load. Treatment with most SMs extended the wax moth larval survival and reduced the intra-larval APEC load. Our studies could facilitate the development of antimicrobial therapeutics for the effective management of APEC infections in poultry as well as other E. coli related foodborne zoonosis, including APEC related ExPEC infections in humans.

SUBMITTER: Kathayat D

PROVIDER: S-EPMC6193035 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Novel small molecules affecting cell membrane as potential therapeutics for avian pathogenic Escherichia coli.

Kathayat Dipak D Helmy Yosra A YA Deblais Loic L Rajashekara Gireesh G

Scientific reports 20181017 1

Avian pathogenic Escherichia coli (APEC), a most common bacterial pathogen of poultry, causes multiple extra-intestinal diseases in poultry which results in significant economic losses to the poultry industry worldwide. In addition, APEC are a subgroup of extra-intestinal pathogenic E. coli (ExPEC), and APEC contaminated poultry products are a potential source of foodborne ExPEC infections to humans and transfer of antimicrobial resistant genes. The emergence of multi-drug resistant APEC strains ...[more]

PMID: 30333507

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Project description:Avian pathogenic Escherichia coli (APEC), an extraintestinal pathogenic E. coli (ExPEC), causes colibacillosis in chickens and is reportedly associated with urinary tract infections and meningitis in humans. Development of resistance is a major limitation of current ExPEC antibiotic therapy. New antibacterials that can circumvent resistance problem such as antimicrobial peptides (AMPs) are critically needed. Here, we evaluated the efficacy of Lactobacillus rhamnosus GG (LGG)-derived peptides against APEC and uncovered their potential antibacterial targets. Three peptides (NPSRQERR [P1], PDENK [P2], and VHTAPK [P3]) displayed inhibitory activity against APEC. These peptides were effective against APEC in biofilm and chicken macrophage HD11 cells. Treatment with these peptides reduced the cecum colonization (0.5 to 1.3 log) of APEC in chickens. Microbiota analysis revealed two peptides (P1 and P2) decreased Enterobacteriaceae abundance with minimal impact on overall cecal microbiota of chickens. Bacterial cytological profiling showed peptides disrupt APEC membranes either by causing membrane shedding, rupturing, or flaccidity. Furthermore, gene expression analysis revealed that peptides downregulated the expression of ompC (>13.0-fold), ompF (>11.3-fold), and mlaA (>4.9-fold), genes responsible for the maintenance of outer membrane (OM) lipid asymmetry. Consistently, immunoblot analysis also showed decreased levels of OmpC and MlaA proteins in APEC treated with peptides. Alanine scanning studies revealed residues crucial (P1, N, E, R and P; P2, D and E; P3, T, P, and K) for their activity. Overall, our study identified peptides with a new antibacterial target that can be developed to control APEC infections in chickens, thereby curtailing poultry-originated human ExPEC infections. IMPORTANCE Avian pathogenic Escherichia coli (APEC) is a subgroup of extraintestinal pathogenic E. coli (ExPEC) and considered a foodborne zoonotic pathogen transmitted through consumption of contaminated poultry products. APEC shares genetic similarities with human ExPECs, including uropathogenic E. coli (UPEC) and neonatal meningitis E. coli (NMEC). Our study identified Lactobacillus rhamnosus GG (LGG)-derived peptides (P1 [NPSRQERR], P2 [PDENK], and P3 [VHTAPK]) effective in reducing APEC infection in chickens. Antimicrobial peptides (AMPs) are regarded as ideal candidates for antibacterial development because of their low propensity for resistance development and ability to kill resistant bacteria. Mechanistic studies showed peptides disrupt the APEC membrane by affecting the MlaA-OmpC/F system responsible for the maintenance of outer membrane (OM) lipid asymmetry, a promising new druggable target to overcome resistance problems in Gram-negative bacteria. Altogether, these peptides can provide a valuable approach for development of novel anti-ExPEC therapies, including APEC, human ExPECs, and other related Gram-negative pathogens. Furthermore, effective control of APEC infections in chickens can curb poultry-originated ExPEC infections in humans.

Project description:Chickens are a major source of protein worldwide, yet infectious diseases continue to threaten the poultry industry. Avian pathogenic Escherichia coli (APEC), a subgroup of extraintestinal pathogenic E. coli (ExPEC), causes colibacillosis in chickens resulting in economic loss because of treatment, condemnation of products, and death. In this study, we evaluated a recombinant antigens (rAg) vaccine combining common ExPEC surface proteins EtsC, OmpA, OmpT, and TraT for broad protective potential against APEC infections in chickens. The specific objectives were to evaluate antibody (serum) and cytokines (lymphoid organs) responses to vaccination; in vitro bactericidal ability of serum and splenocytes against multiple APEC serotypes; and in vivo protection against APEC challenge in chickens. Groups of four-day old chickens (N = 10) were vaccinated twice (two-week interval) subcutaneously with rAgs alone or in combination and CpG adjuvant or PBS (control). IgY antibody in the serum and mRNA expression of IL-1β, IL-6, IL-18, IFN-γ, IL-4, IFN-β, and IL-8 in bursa, spleen, and thymus were measured using ELISA and RT-qPCR, respectively. Serum and splenocytes were tested for their bactericidal ability in vitro against multiple APEC isolates. Vaccinated and non-vaccinated chickens were challenged with 108 CFU of APEC-O2 via air sac at 31 days post first vaccination. Vaccine protection was determined by the decrease of bacterial loads in blood and organs (lung, heart, spleen, and liver), as well as gross colibacillosis lesion scores in air sac, heart, and liver. Vaccination significantly (P < 0.05) elicited IgY against specific antigens, induced immune related mRNA expression in the spleen and bursa, reduced in vitro growth of multiple APEC serotypes, and decreased bacterial loads in the heart and spleen, and gross lesion scores of the air sac, heart and liver in chickens. The vaccine reported may be used to provide broad protection against APEC strains, increasing animal welfare and food production.

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Novel small molecules affecting cell membrane as potential therapeutics for avian pathogenic Escherichia coli.

Publications

Novel small molecules affecting cell membrane as potential therapeutics for avian pathogenic Escherichia coli.

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