A proteogenomic view on antibiotic resistance in pathogenic Enterobacter species

Bacteria belonging to the family of Enterobacteriaceae are renowned for causing bloodstream infections, hospital- and healthcare-associated pneumonia, intra-abdominal infections, and urinary tract infections. These infections are usually effectively fought with antibiotics. However, certain Enterobacteriaceae produce enzymes that make them invulnerable, even to the so-called carbapenems, which are antibiotics with an exceptionally broad spectrum of bactericidal activity. Accordingly, carbapenems are considered as “last resort” antibiotics. Today, carbapenem resistant bacteria are a worldwide threat for healthcare settings, especially since infections caused by these highly antibiotic resistant pathogens are nearly untreatable and associated with high mortality rates. The present thesis describes studies on Enterobacteriaceae, belonging to the Enterobacter cloacae complex, which were remarkable either because they were highly carbapenem resistant, or because they were associated with unusual bone infections. The results show that carbapenem resistance in the investigated bacteria was acquired by horizontal transfer of carbapenemase genes, involving a thus far overlooked ancient mobile genomic element or a novel megaplasmid with many additional antibiotic resistance genes. Moreover, by applying integrated in-depth genomics and proteomics analyses, other factors were found to contribute to carbapenem resistance, including restricted cell envelope permeability, reduced metabolism, limited formation of reactive oxygen species, and increased antioxidant production. On the other hand, isolates associated with bone infections were sensitive to most antibiotics, but expressed a large array of virulence factors. Altogether, the present studies have greatly increased our understanding of antibiotic resistance mechanisms and virulence in Enterobacteriacea that belong to the E. cloacae complex.