Abstract
Acinetobacter baumannii is a challenging pathogen due to antimicrobial resistance and biofilm development. The role of iron in bacterial physiology has prompted the evaluation of iron-modulation as an antimicrobial strategy. The non-reducible iron analog gallium(III) nitrate, Ga(NO3)3, has been shown to inhibit A. baumannii planktonic growth; however, utilization of heme-iron by clinical isolates has been associated with development of tolerance. These observations prompted the evaluation of iron-heme sources on planktonic and biofilm growth, as well as antimicrobial activities of gallium meso- and protoporphyrin IX (Ga-MPIX and Ga-PPIX), metal heme derivatives against planktonic and biofilm bacteria of multidrug-resistant (MDR) clinical isolates of A. baumannii in vitro. Ga(NO3)3 was moderately effective at reducing planktonic bacteria (64 to 128 µM) with little activity against biofilms (≥512 µM). In contrast, Ga-MPIX and Ga-PPIX were highly active against planktonic bacteria (0.25 to 8 µM). Cytotoxic effects in human fibroblasts were observed following exposure to concentrations exceeding 128 µM of Ga-MPIX and Ga-PPIX. We observed that the gallium metal heme conjugates were more active against planktonic and biofilm bacteria, possibly due to utilization of heme-iron as demonstrated by the enhanced effects on bacterial growth and biofilm formation.
Highlights
Acinetobacter baumannii is an important and problematic pathogen, emerging as a significant cause of community-acquired and nosocomial infections, amongst critically ill patients in intensive care units [1,2,3]
As well paucity of data on activity of gallium on biofilms, we evaluated the antimicrobial activities of the gallium heme-porphyrins, gallium mesoporphyrin IX (Ga-MPIX) and gallium protoporphyrin IX (Ga-PPIX), against planktonic and biofilm bacteria of clinical MDR A. baumannii isolates
Given the recent observations of utilization of heme iron by clinical isolates of A. baumannii and its contribution to Ga(NO3)3 tolerance in vitro [35], Pharmaceuticals 2016, 9, 16 we initially evaluated the effect of heme iron and non-heme iron sources on bacterial growth as well as biofilm formation in vitro
Summary
Acinetobacter baumannii is an important and problematic pathogen, emerging as a significant cause of community-acquired and nosocomial infections, amongst critically ill patients in intensive care units [1,2,3]. While several studies have demonstrated the success of modulating iron availability for various pathogens using iron chelators, including desferoxamine (DFO), deferiprone, and 2,2-dipyridyl (DIP) as an antimicrobial strategy, only recently has this approach been extended to A. baumannii Reports have demonstrated their limited and highly variable antimicrobial activity against clinical strains [27,28]. While studies have supported the use of Ga(NO3) as a potential antimicrobial therapy for A. baumannii, more recent studies have shown that utilization of heme-iron sources by clinical strains of A. baumannii can contribute to the development of tolerance to gallium alone [35] Given these observations, as well paucity of data on activity of gallium on biofilms, we evaluated the antimicrobial activities of the gallium heme-porphyrins, gallium mesoporphyrin IX (Ga-MPIX) and gallium protoporphyrin IX (Ga-PPIX), against planktonic and biofilm bacteria of clinical MDR A. baumannii isolates
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