Abstract
In light of the ongoing antimicrobial resistance crisis, there is a need to understand the role of co-pathogens, commensals, and the local microbiome in modulating virulence and antibiotic resistance. To identify possible interactions that influence the expression of virulence or survival mechanisms in both the multidrug-resistant organisms (MDROs) and human host cells, unique cohorts of clinical isolates were selected for whole genome sequencing with enhanced assembly and full annotation, pairwise co-culturing, and transcriptome profiling. The MDROs were co-cultured in pairwise combinations either with: (1) another MDRO, (2) skin commensals (Staphylococcus epidermidis and Corynebacterium jeikeium), (3) the common probiotic Lactobacillus reuteri, and (4) human fibroblasts. RNA-Seq analysis showed distinct regulation of virulence and antimicrobial resistance gene responses across different combinations of MDROs, commensals, and human cells. Co-culture assays demonstrated that microbial interactions can modulate gene responses of both the target and pathogen/commensal species, and that the responses are specific to the identity of the pathogen/commensal species. In summary, bacteria have mechanisms to distinguish between friends, foe and host cells. These results provide foundational data and insight into the possibility of manipulating the local microbiome when treating complicated polymicrobial wound, intra-abdominal, or respiratory infections.
Highlights
The emergence of Multiple Drug Resistant Organisms (MDROs) that exhibit resistance to at least three classes of antibiotics[1], and the frequency of serious infections caused by multidrug-resistant organisms (MDROs) combined with the lack of development and approval of new antibiotics has led the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) to declare that antimicrobial resistance poses an urgent threat to global public health[2,3,4]
MDROs used in this study were selected by collaborators at the Walter Reed Army Institute of Research (WRAIR) Multidrug-resistant Organism Repository and Surveillance Network (MRSN) as having one or more of the following characteristics: polytraumatic blast injuries, initial injuries in Afghanistan or Iraq, multi-drug resistant, isolated from traumatic wound surfaces or surveillance culture, and/or outbreak in the DOD health system from 2003–2015
Bacteria considered human commensals and members of the human skin microbiome were chosen as confronting partners if they can be cultured aerobically at 37 °C and on media similar to the selected MDROs, and if their genome sequence was publicly available
Summary
The emergence of Multiple Drug Resistant Organisms (MDROs) that exhibit resistance to at least three classes of antibiotics[1], and the frequency of serious infections caused by MDROs combined with the lack of development and approval of new antibiotics has led the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) to declare that antimicrobial resistance poses an urgent threat to global public health[2,3,4]. Klebsiella pneumoniae, Acinetobacter baumannii, and Enterobacter species are some of the most challenging MDROs to treat, especially when they are isolated with other co-pathogens and/or commensals from polymicrobial respiratory, intra-abdominal and wound infections[8,9,10] These organisms have evolved and/or horizontally acquired a diverse arsenal of resistance mechanisms[11], including transmembrane transporters known as efflux pumps, drug neutralizing enzymes such the carbapenemases[12] and extended spectrum beta-lactamases[13,14], and mutations in ribosomal RNA (rRNA)[15] or topoisomerase genes[16] to escape the target of the drug. Microbial communities consist of multiple species in commensal or symbiotic coexistence where cells can communicate via quorum sensing and influence interactions with each other To detect these biological interactions, classical studies have used co-culture assays to monitor the effects of a pathogen/commensal species on the growth or survival of the target species. The primary goal was to identify and characterize interactions among bacteria and host that influence the expression of virulence factors and antimicrobial resistance (AMR) in MDROs
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