MgrB-Dependent Colistin Resistance in Klebsiella pneumoniae Is Associated with an Increase in Host-to-Host Transmission

Abstract

ABSTRACT Due to its high transmissibility, Klebsiella pneumoniae is one of the leading causes of nosocomial infections. Here, we studied the biological cost of colistin resistance, an antibiotic of last resort, in this opportunistic pathogen using a murine model of gut colonization and transmission. Colistin resistance in K. pneumoniae is commonly the result of the inactivation of the small regulatory protein MgrB. Without a functional MgrB, the two-component system PhoPQ is constitutively active, leading to an increase in lipid A modifications and subsequent colistin resistance. Using an isogenic mgrB deletion mutant (MgrB−), we demonstrate that the mutant’s colistin resistance is not associated with a fitness defect under in vitro growth conditions. However, in our murine model of K. pneumoniae gastrointestinal (GI) colonization, the MgrB− colonizes the gut poorly, allowing us to identify a fitness cost. Moreover, the MgrB− mutant has higher survival outside the host compared with the parental strain. We attribute this enhanced survivability to dysregulation of the PhoPQ two-component system and accumulation of the master stress regulator RpoS. The enhanced survival of MgrB− may be critical for its rapid host-to-host transmission observed in our model. Together, our data using multiple clinical isolates demonstrate that MgrB-dependent colistin resistance in K. pneumoniae comes with a biological cost in gut colonization. However, this cost is mitigated by enhanced survival outside the host and consequently increases its host-to-host transmission. Additionally, it underscores the importance of considering the entire life cycle of a pathogen to determine the actual biological cost associated with antibiotic resistance. IMPORTANCE The biological cost associated with colistin resistance in Klebsiella pneumoniae was examined using a murine model of K. pneumoniae gut colonization and fecal-oral transmission. A common mutation resulting in colistin resistance in K. pneumoniae is a loss-of-function mutation of the small regulatory protein MgrB that regulates the two-component system PhoPQ. Even though colistin resistance in K. pneumoniae comes with a fitness defect in gut colonization, it increases bacterial survival outside the host enabling it to transmit more effectively to a new host. The enhanced survival is dependent upon the accumulation of RpoS and dysregulation of the PhoPQ. Hence, our study expands our understanding of the underlying molecular mechanism contributing to the transmission of colistin-resistant K. pneumoniae.

Keywords

• antimicrobial peptides
• gastrointestinal infection
• host-to-host transmission
• infection control
• stress adaptation
• two-component regulatory systems