Dual Gallium Drug Treatment Against Carbapenem-Resistant Klebsiella Pneumoniae: Efficacy and Potential Mechanism(s) of Action and Resistance

Abstract

Klebsiella pneumoniae (KLP) is a Gram-negative pathogen that can be highly antibiotic-resistant. Our group has worked with gallium-based compounds as a means of treating bacterial infections. Here the possible mechanism is investigated for dual therapy comprised of gallium nitrate (Ga(NO₃)₃) and gallium protoporphyrin (GaPP) on KLP. It is found that in vitro the combination of Ga(NO₃)₃ and GaPP is synergistic against KLP. The in vivo efficacy is of the dual therapy is additionally tested by treating pulmonary KLP infections in mice. Much greater effectiveness are observed in bacterial clearance and survival of mice receiving the dual therapy than that of singly treated or untreated mice. It is found that in in vitro the dual therapy increased reactive oxygen stress in treated bacteria. Combination therapy impacted KLP catalase, but not superoxide dismutase (SOD) activity. Finally, alterations in KLP genes encoding 6-phosphogluconate phosphatase or cytochrome C assembly protein are found to be associated with increased resistance to combination gallium therapy, raising the MIC to both Ga(NO₃)₃ and GaPP by 4-fold. These cumulative data lend validation to the potential for the use of Ga(NO₃)₃ and GaPP combination therapy against KLP and suggest that increased oxidative stress is involved in the mechanism of action.