Bacterial infections are highly prevalent and contribute significantly to morbidity and mortality across all age-groups but because appropriate microbiologic diagnostic services are non- existent or very limited, ascertaining the specific etiologic agents and the true prevalence of antimicrobial resistance (AMR) is a major challenge in Africa, where objective data is limited. Preliminary observations from Nigeria, the most populous country in Africa include the following; a) High prevalence of Salmonella enterica serovar Typhi (S. Typhi) with 45% prevalence of multidrug resistance, b) High prevalence of Extended Spectrum β-Lactamase- producing Enterobacteriaceae (ESBL-E) blood stream infections, c) Maternal colonization by ESBL-E in women at delivery is associated with high all-cause morbidity and mortality in their newborn babies compared to ESBL-unexposed babies and d) Periodic outbreaks of carbapenem-resistant Klebsiella pneumoniae sepsis in newborn units with case fatality rates as high as 45%. We have preliminary molecular characterization of about 500 of the 2,750 diverse bloodstream bacterial isolates in our collection. In addition, we have access to a collection of over 2,500 clinical isolates of blood, sputum and urine from our sentinel laboratories in Nigeria and Rwanda that are partially characterized. Our unique observations related to AMR genes that we have identified in our archived isolates form the basis for this research proposal. Our overall strategy in this application focuses on three thematic areas: 1). Comparative phenotypic and genotypic studies of archived and contemporary clinical isolates to inform trends in AMR and dynamics of transmission. 2) Incorporation of acute inflammatory markers of serious bacterial infection and gene products from resistant bacteria into a portable screening tool for clinical care and 3). Explore the potential benefit of an aminoglycoside (Tobramycin) conjugated to an antimicrobial peptide for enhanced bactericidal activity against multi-drug resistant enterobacteriales. We have assembled a multidisciplinary team of clinical and molecular microbiologists, clinicians, biomedical engineers, environmental microbiologists, veterinarians, and industrialists to implement this project in Nigeria, West Africa and also Rwanda, East Africa to provide data with geographic representation for Africa. Upon successful completion of this program, we would have utilized the data science platform for bacteria genomics and antimicrobial resistance to raise awareness on the scope of AMR in Africa, provide novel pathways for optimizing empiric use of antibiotics and trained a handful of young African scientists in bacterial genomics and bioinformatics.

Project Narrative Bacterial infections are highly prevalent and contribute significantly to morbidity and mortality across all age-groups but because appropriate bacterial diagnostic services are non- existent or very limited, finding the true cause of most infections and the true spread of antimicrobial resistance (AMR) is a major challenge in Africa, where data is limited. Our proposal has three goals to comparatively study bacterial isolates to inform trends in AMR and dynamics of transmission, to incorporate markers of serious bacterial infection and gene products from resistant bacteria to create a portable screening tool for clinical care and to explore the antimicrobial propers, and to explore the potential benefit of an aminoglycoside-antimicrobial peptide complex for enhanced therapeutic efficacy against multidrug resistant bacteria.