Asrat, Daniel(PhD)Eingidawork, Ephrem (PhD)Eguale, Tadesse2018-06-272023-11-062018-06-272023-11-062016-06http://etd.aau.edu.et/handle/123456789/3999This dissertation reports prevalence, serotype distribution and phenotypic and genotypic characteristics of non-typhoidal Salmonella (NTS) in humans and animals in central Ethiopia and effect of small molecule adenosine mimetic compounds on Salmonella biofilm formation. Farm level and animal level Salmonella prevalence was (7.6%, 2.3%) in dairy; (14.6%, 4.7%) in poultry; and (42.6%, 4.4%) in swine farms. The prevalence was 7.2% in diarrheic patients from primary health centers and 2.1% from hospitals. S.Typhimurium (27.6%) was the most frequently isolated serotype, followed by S. Saintpaul (21.7%), S. Virchow (18.4%) and S. Kentucky (6.6%). Salmonella isolation was significantly associated with detection of diarrhea in dairy cattle (p=0.012), and consumption of raw vegetables in humans (OR=1.91, 95% CI=1.29-2.83, χ2=4.74, p=0.025). Drug resistance was more common in dairy farms in Addis Ababa than outside (p=0.009) and overall antimicrobial resistance was more common in animals than in humans. Clonally related genotypes of S.Virchow, S.Typhimurium, S.Kentucky, S.Braendurp and S. Miami were circulating among humans and animals as determined by pulsed-field gel electrophoresis (PFGE). MLST analysis showed 3 novel allele types and 5 novel sequence types among 21 strains examined. The dominant beta-lactamase enzyme was blaTEM type. BlaOXA10 and blaCTX-15 were detected only in a single MDR S. Concord strain. Double mutation in gyrA (Ser83-Phe and Asp87-Gly) as well as parC (Thr57-Ser + Ser80-Ile) subunits of quinolone resistance determining region (QRDR) was the primary mechanism for resistance to quinolones and was detected in all S. Kentucky isolates resistant to both nalidixic acid and ciprofloxacin from animals (n=8) and humans (n=2). Although decreased susceptibility to ciprofloxacin and/or nalidixic acid was observed in some isolates, no mutation in QRDR nor plasmid mediated quinolone resistance (PMQR) genes were detected. Majority of Salmonella ii isolates exhibited robust biofilm formation (89%) and displayed red dry and rough (RDAR) morphotype. Detection of class 1 integron was correlated with expression of multicellular behavior and the extent of MDR. Screening of an ATP-mimetic library, gave a single compound (7955004) capable of significant inhibition of Salmonella enterica and Acinetobacter baumannii biofilm formation. The compound was not bactericidal or bacteriostatic toward S. Typhimurium nor cytotoxic to mammalian cells. GroEL and DeoD were found to be the potential protein-binding targets of the compound as identified by ATP-sepharose affinity matrix. Circulation of clonally related NTS serotypes in food animals and humans, abundance of MDR in isolates from food animals, co-dominance of MDR and multicellular behavior in Salmonella isolates in the study area, increased the risk of spreading resistant Salmonella strains and resistance genes to human population. Integrated surveillance of NTS in humans and animals and implementation of appropriate pathogen control strategy along critical points in food animal production from farm to bench is recommended. The identification of a lead compound with biofilm inhibitory capabilities toward Salmonella provides a potential new avenue of therapeutic intervention against Salmonella and other bacterial pathogens. Further activity guided evaluation of compound 7955004 and its derivatives with the goal of increasing its potency and broadening its spectrum of activity against additional biofilm forming pathogens should be conducted. Key words: Antimicrobial resistance, Biofilm, Non-typhoidal Salmonella, Prevalence, SerotypeenAntimicrobial resistanceBiofilm, Non-typhoidal SalmonellaPrevalenceThesis