The Antimicrobial Activity of a Carbon Monoxide Releasing Molecule (EBOR-CORM-1) Is Shaped by Intraspecific Variation within Pseudomonas aeruginosa Populations

Abstract

Carbon monoxide releasing molecules (CORMs) have been suggested as a new synthetic class of antimicrobials to treat bacterial infections. Here we utilized a novel EBOR-CORM-1 ([NEt4][MnBr2(CO)4]) capable of water-triggered CO-release, and tested its efficacy against a collection of clinical Pseudomonas aeruginosa strains that differ in infection-related virulence traits. We found that while EBOR-CORM-1 was effective in clearing planktonic and biofilm cells of P. aeruginosa strain PAO1 in a concentration dependent manner, this effect was less clear and varied considerably between different P. aeruginosa cystic fibrosis (CF) lung isolates. While a reduction in cell growth was observed after 8 h of CORM application, either no effect or even a slight increase in cell densities and the amount of biofilm was observed after 24 h. This variation could be partly explained by differences in bacterial virulence traits: while CF isolates showed attenuated in vivo virulence and growth compared to strain PAO1, they formed much more biofilm, which could have potentially protected them from the CORM. Even though no clear therapeutic benefits against a subset of isolates was observed in an in vivo wax moth acute infection model, EBOR-CORM-1 was more efficient at reducing the growth of CF isolate co-culture populations harboring intraspecific variation, in comparison with efficacy against more uniform single isolate culture populations. Together these results suggest that CORMs could be effective at controlling genetically diverse P. aeruginosa populations typical for natural chronic CF infections and that the potential benefits of some antibiotics might not be observed if tested only against clonal bacterial populations.

Emerging Delivery Strategies of Carbon Monoxide for Therapeutic Applications: from CO Gas to CO Releasing Nanomaterials

“…For example, Nobre et al reported that the administration of CO gas into the growing cultures could cause significant impairment to the growth of Escherichia coli and Staphylococcus aureus . Recently, CORMs with the capacity of delivering CO directly to intracellular targets have been used as bactericides against a wide range of microorganisms, such as Pseudomonas aeruginosa , Mycobacterium tuberculosis , Helicobacter pylori , pathogenic Escherichia coli , and Neisseria gonorrhoeae . Importantly, CORMs were shown to be more potent bactericides than CO gas due to the accumulation of CORMs inside bacterial cells .…”

Biological activity of manganese(i) tricarbonyl complexes on multidrug-resistant Gram-negative bacteria: From functional studies to in vivo activity in Galleria mellonella

“…[3] CO is rarely metabolized and is therefore 'stable', reasonably watersoluble and readily traverses cell membranes. CORMs are reported to be effective antibacterial agents, either alone [15][16][17][18][19][20] or in combination with other antibacterial agents. [21][22] The expanding number of new CORMs and their potential have been seen as promising advances, but some recent data cast doubt on the underlying mechanisms.…”

Targeting the Heme Oxygenase 1/Carbon Monoxide Pathway to Resolve Lung Hyper-Inflammation and Restore a Regulated Immune Response in Cystic Fibrosis

“…We and others have shown that CO-RMs are effective at killing or aiding in the killing of P. aeruginosa clinical strains recovered from CF patients and grown in liquid culture or in biofilms (Murray et al, 2012;Flanagan et al, 2018). However, these studies also show that certain P. aeruginosa clinical isolates are less susceptible to CO (Murray et al, 2012;Flanagan et al, 2018). Moreover, the bacterial growth conditions influence CO's effectiveness.…”

“…Along with the previously discussed stimulation of the host cells, CO treatment has an additional potential clinical benefit in its direct bactericidal activity. Multiple studies have documented that CO and CO-RM treatment results in killing of a variety of pathogenic bacteria including P. aeruginosa, E. coli, Salmonella enterica, S. aureus, and Helicobacter pylori (Nobre et al, 2007;Murray et al, 2012;Bang et al, 2014;Rana et al, 2014;Flanagan et al, 2018). This has generally been true regardless of the carrier molecule used to deliver the CO, which accumulates inside bacterial cells before they release CO (Nobre et al, 2016).…”