Sugar administration is an effective adjunctive therapy in the treatment ofPseudomonas aeruginosapneumonia

Abstract

Treatment of acute and chronic pulmonary infections caused by opportunistic pathogen Pseudomonas aeruginosa is limited by the increasing frequency of multidrug bacterial resistance. Here, we describe a novel adjunctive therapy in which administration of a mix of simple sugars-mannose, fucose, and galactose-inhibits bacterial attachment, limits lung damage, and potentiates conventional antibiotic therapy. The sugar mixture inhibits adhesion of nonmucoid and mucoid P. aeruginosa strains to bronchial epithelial cells in vitro. In a murine model of acute pneumonia, treatment with the sugar mixture alone diminishes lung damage, bacterial dissemination to the subpleural alveoli, and neutrophil- and IL-8-driven inflammatory responses. Remarkably, the sugars act synergistically with anti-Pseudomonas antibiotics, including β-lactams and quinolones, to further reduce bacterial lung colonization and damage. To probe the mechanism, we examined the effects of sugars in the presence or absence of antibiotics during growth in liquid culture and in an ex vivo infection model utilizing freshly dissected mouse tracheas and lungs. We demonstrate that the sugar mixture induces rapid but reversible formation of bacterial clusters that exhibited enhanced susceptibility to antibiotics compared with individual bacteria. Our findings reveal that sugar inhalation, an inexpensive and safe therapeutic, could be used in combination with conventional antibiotic therapy to more effectively treat P. aeruginosa lung infections.

Mimicking the host and its microenvironmentin vitrofor studying mucosal infections byPseudomonas aeruginosa

“…At the other extreme are animal models, which have advanced our knowledge on various P. aeruginosa ‐induced illnesses, but often do not mimic human physiology and disease, are complex and require extensive expertise. As many in vitro findings have been confirmed using animal models (Pier et al ., , b; Martin et al .,; Bucior et al ., ; Cory et al ., ), it is relevant to utilize in vitro model systems to initially explore fundamental questions and to verify select findings in vivo . This approach can significantly refine and reduce the use of animal models.…”

Mechanisms of phagocytosis and host clearance ofPseudomonas aeruginosa

“…Nonopsonic phagocytosis is a crucial mechanism for host control during the initial stages of infection, and mouse models indicate that this process may dictate colonization efficiency at the onset of P. aeruginosa challenge (4). Whereas recent reports and reviews have detailed various other components of P. aeruginosa respiratory disease, such as pulmonary edema, humoral immunity, and therapeutic avenues (10,16,20,31,32,46,51,61,73,88,96,102,110,122), this review will spotlight the current state of knowledge in nonopsonic phagocytic recognition and response mechanisms to P.…”

Considerations and caveats in anti-virulence drug development

“…Anti-biofilm inhibitors targeting carbohydrate-binding lectins show good potency in vitro and in vivo , but might disrupt host lectins [27,36]. Type IV pili [37] are unsuitable targets because they are not well-conserved in P. aeruginosa isolates.…”