Synergistic interactions of ruthenium-based carbon monoxide-releasing molecules and antibiotics in their effects on Escherichia coli

The emergence of antibiotic-resistant pathogenic bacteria poses a major and growing public health risk. Because antibiotics act on specific molecular targets, bacteria may evolve resistance mechanisms that alter or bypass these targets. This work investigated the antimicrobial effects of carbon monoxide-releasing molecules (CORMs) and their potential for co-administration with a variety of commonly used antibiotics against <i>Escherichia coli</i>. CORMs, commonly transition metal carbonyls, release carbon monoxide under certain conditions. Interestingly, CORMs have been shown to exert antimicrobial activity against bacteria both <i>in vitro</i> and <i>in vivo</i>. However, to effectively treat patients with antibiotic-resistant infections, combination therapies involving two or more antimicrobial agents may be a useful approach. Herein, we report the antimicrobial activity of CORM-2 and CORM-3 against <i>E. coli</i> and, importantly, that sub-inhibitory concentrations of either compound in combination with antibiotics showed a significant increase in efficacy of the conventional antibiotics as assessed by inhibition of bacterial growth and reduced viability. Furthermore, administration of sub-inhibitory concentrations of CORMs increased the antimicrobial activity of multiple antibiotics with a range of modes of action when measured by E-tests and microdilution broth assays. The minimal bactericidal concentrations were reduced 2- to 8-fold and 10- to 63-fold for CORM-2 and CORM-3, respectively. Drug interactions between CORMs and antibiotics were also assessed using checkerboard microdilution methods, providing evidence that CORM activity is synergistic with a wide range of conventional antibiotics tested with fractional inhibitory concentration indices between 0.31 and 0.45. These findings demonstrate the antibacterial activity of CORMs and their synergy with a range of commonly used antibiotics, opening potential avenues for CORMs to be used as adjuvants to traditional antibiotic treatments.