Prophylaxis and Treatment against Klebsiella pneumoniae: Current Insights on This Emerging Anti-Microbial Resistant Global Threat

Abstract

Klebsiella pneumoniae (Kp) is an opportunistic pathogen and the leading cause of healthcare-associated infections, mostly affecting subjects with compromised immune systems or suffering from concurrent bacterial infections. However, the dramatic increase in hypervirulent strains and the emergence of new multidrug-resistant clones resulted in Kp occurrence among previously healthy people and in increased morbidity and mortality, including neonatal sepsis and death across low- and middle-income countries. As a consequence, carbapenem-resistant and extended spectrum β-lactamase-producing Kp have been prioritized as a critical anti-microbial resistance threat by the World Health Organization and this has renewed the interest of the scientific community in developing a vaccine as well as treatments alternative to the now ineffective antibiotics. Capsule polysaccharide is the most important virulence factor of Kp and plays major roles in the pathogenesis but its high variability (more than 100 different types have been reported) makes the identification of a universal treatment or prevention strategy very challenging. However, less variable virulence factors such as the O-Antigen, outer membrane proteins as fimbriae and siderophores might also be key players in the fight against Kp infections. Here, we review elements of the current status of the epidemiology and the molecular pathogenesis of Kp and explore specific bacterial antigens as potential targets for both prophylactic and therapeutic solutions.

Keywords: Klebsiella pneumoniae; anti-microbial resistance; monoclonal antibodies; vaccines.

Figure 1

K. pneumoniae virulence factors. There are four well-characterized virulence factors for pathogenic Klebsiella pneumoniae (Kp). (1) The capsule is an extracellular polysaccharide matrix that envelops the bacteria and is overproduced in hypervirulent Kp (Hv-Kp) strains. (2) Lipopolysaccharide (LPS) is an integral part of the outer leaflet of the outer membrane and is produced by both classical and Hv-Kp strains. (3) Type 1 and type 3 fimbriae are membrane-bound adhesive structures. (4) Iron-scavenging siderophores are secreted small molecules recognized by specific membrane receptors mediating their uptake. Enterobactin is produced by virtually all Kp strains while other siderophores are typically secreted by Hv-Kp strains.

Figure 2

(A) Model for biosynthesis and assembly of group 1 capsules. Undecaprenol-pyrophosphate (Und-PP)-linked repeating units are assembled on the cytoplasmic leaflet of the inner membrane. Wzx then flips the newly synthesized und-PP-linked repeats across the inner membrane. In the periplasmic leaflet of the inner membrane, Wzy polymerizes the repeating units. Continued polymerization requires transphosphorylation of the Wzc oligomer and dephosphorylation by the Wzb phosphatase. Finally, the polysaccharide is translocated by Wza in the extracellular milieu where it associates with the surface protein Wzi. PP = Undecaprenyl diphosphate, GT = glycosyltransferase. (B) Structures of K-antigens most commonly associated to Hv-Kp strains.

Figure 3

(A) Model of O-antigen biosynthesis via the adenosine triphosphate-binding cassette (ABC) transporter pathway. Und-PP-linked O-polyaccharides are processively assembled on the cytoplasmic leaflet of the inner membrane, through the sequential activity of different glycosyltransferases. The assembled O-antigen component is then transported via the Wzm/Wzt ABC transporter across the inner membrane. In the periplasmic leaflet of the inner membrane, the O-antigen is ligated to the lipid A-core oligosaccharide by WaaL and finally transported on the bacterial surface by the Lpt complex. (B) Structures of Kp O-antigens.