Pathogens are of significant importance in medicine and public health, as they are responsible for a wide range of infectious diseases that can have serious consequences for human and animal populations. Whether infection gets established, depends on multiple factors, including environment, the host, and interactions with other bacteria. Understanding these factors and their impact is a prerequisite for developing therapies for resisting or disarming pathogenic bacteria. Adhesins are proteins present on the microbial cell surface that mediate the interactions with or attachment to the host or substance. As one type of virulence factors, adhesin proteins play a crucial role in the ability of the fungal pathogen Candida albicans to undergo cellular morphogenesis, develop robust biofilms, colonize, and cause infection in a host. By performing a comprehensive, high-throughput screen of a library of adhesin mutants in the model nematode Caenorhabditis elegans as a simplified host system, I identified mutants critical for virulence of C. albicans. Colonization is generally considered a prerequisite for infection, but this event is context-dependent, as evidenced by the differing ability of the human pathogen Pseudomonas aeruginosa to efficiently colonize C. elegans on agar but not in liquid pathogenesis. I showed that the transition to a liquid environment reduces food uptake, decreases specific adhesins, slightly upregulates host immunity, and induces a pathogen-driven dormancy of C. elegans, which restricts pathogenic colonization. My study also found that pathogenic colonization was still required for the virulence of Enterococcus faecalis even in the liquid. I conclude that poor colonization in liquid is likely due to a combination of environmental factors and host-pathogen interactions. These results provide new insights into mechanisms for colonization in different models, enabling pathogenesis models to be fine-tuned to more accurately represent the conditions seen in human infections so that new tools for curbing bacterial and fungal infections can be developed. Competition shapes the life spectrum in nature, resulting in organisms with better fitness taking a position of dominance and prevalence. The high-risk clone of P. aeruginosa ST111 predominates in hematopoietic cell transplant and hematologic malignancy (HCT/HM) bloodstream infection (BSI) patients via a fitness benefit due to the loss of functional OprD, a porin responsible for the import of carbapenems. Further study revealed that not only ST111 but also several international high-risk sequence types produce the bactericidal R5 pyocin that targets P. aeruginosa with mutations on WaaL, an O-antigen ligase of lipopolysaccharide. These findings suggest a novel approach for evaluating risks associated with emerging prevalent P. aeruginosa strains and may inform the development of strategies to mitigate the impact of ST111 and other high-risk clones on public health. In conclusion, my dissertation research provides valuable insights into the virulence of pathogens and their interactions with the host. Having a thorough understanding of the features of each infection model can power researchers to do pathogenesis research and hereby develop effective treatments or interventions for infectious diseases. The identification of R5 pyocin producers and their fitness benefits in causing infection highlights the need for ongoing monitoring and surveillance to inform public health strategies to mitigate the impact of emerging pathogens on human health.