Re-sensitizing Ampicillin and Kanamycin-Resistant E. coli and S. aureus Using Synergistic Metal Micronutrients-Antibiotic Combinations

Abstract

Due to the recent emergence of multi-drug resistant strains, the development of novel antimicrobial agents has become a critical issue. The use of micronutrient transition metals is a promising approach to overcome this problem since these compounds exhibit significant toxicity at low concentrations in prokaryotic cells. In this work, we demonstrate that at concentrations lower than their minimal inhibitory concentrations and in combination with different antibiotics, it is possible to mitigate the barriers to employ metallic micronutrients as therapeutic agents. Here, we show that when administered as a combinatorial treatment, Cu 2+ , Zn 2+ , Co 2+ , Cd 2+ , and Ni 2+ increase susceptibility of Escherichia coli and Staphylococcus aureus to ampicillin and kanamycin. Furthermore, ampicillin-resistant E. coli is re-sensitized to ampicillin when the ampicillin is administered in combination with Cu 2+ , Cd 2+ , or Ni 2 . Similarly, Cu 2+ , Zn 2+ , or Cd 2+ re-sensitize kanamycin-resistant E. coli and S. aureus to kanamycin when administered in a combinatorial treatment with those transition metals. Here, we demonstrate that for both susceptible and resistant bacteria, transition-metal micronutrients, and antibiotics interact synergistically in combinatorial treatments and exhibit increased effects when compared to the treatment with the antibiotic alone. Moreover, in vitro and in vivo assays, using a murine topical infection model, showed no toxicological effects of either treatment at the administered concentrations. Lastly, we show that combinatorial treatments can clear a murine topical infection caused by an antibiotic-resistant strain. Altogether, these results suggest that antibiotic-metallic micronutrient combinatorial treatments will play an important role in future developments of antimicrobial agents and treatments against infections caused by both susceptible and resistant strains.

Antibacterial activity and carbapenem re‐sensitizing ability of 1,10‐phenanthroline‐5,6‐dione and its metal complexes against KPC‐producingKlebsiella pneumoniaeclinical strains

“…The in vitro evaluation of compound combinations is a multitarget strategy that has been explored increasingly as a tactic to eliminate MDR pathogens (Zhang et al 2019;Garza-Cervantes et al 2020). Using the checkerboard method, we investigated the effects of combinations of carbapenems with the phendione compounds against nine non-clonally related clinical strains of Kp-KPC.…”

“…Moreover, experimental data suggests that combination therapy could deaccelerate the onset of bacterial resistance and also reduce toxic side effects as similar levels of antimicrobial efficacy could be attained with lower drug concentrations (Sheard et al 2019;Coates et al 2020). Although synergistic combinations are the most widely reported, recent studies have demonstrated the potential of combining traditional antimicrobials with compounds that potentiate or restore the antibiotic activity of the clinical agent by re-sensitizing strains to the drugs to which they have become resistant (Djoko et al 2018;Minrovic et al 2019;Garza-Cervantes et al 2020). The re-sensitizing combinatorial tactic (repurposing existing agents) greatly accelerates the discovery and development of new therapies (Wright 2016;Garza-Cervantes et al 2020).…”

“…Although synergistic combinations are the most widely reported, recent studies have demonstrated the potential of combining traditional antimicrobials with compounds that potentiate or restore the antibiotic activity of the clinical agent by re-sensitizing strains to the drugs to which they have become resistant (Djoko et al 2018;Minrovic et al 2019;Garza-Cervantes et al 2020). The re-sensitizing combinatorial tactic (repurposing existing agents) greatly accelerates the discovery and development of new therapies (Wright 2016;Garza-Cervantes et al 2020). In summary, the examination of synergistic and re-sensitizing combinations, achieving multitarget engagement, old-drug recycling and suppressing the evolution of resistance could provide the solution for combatting MDR pathogens (Wright 2016;Cheesman et al 2017).…”

“…2019; Garza‐Cervantes et al . 2020). The re‐sensitizing combinatorial tactic (repurposing existing agents) greatly accelerates the discovery and development of new therapies (Wright 2016; Garza‐Cervantes et al .…”

The Demand for New Antibiotics: Antimicrobial Peptides, Nanoparticles, and Combinatorial Therapies as Future Strategies in Antibacterial Agent Design

“…coli using transition-metal micronutrients (Cu2+, Zn2+, Co2+, Cd2+, and Ni2+) combined with antibiotics (ampicillin and kanamycin). These combinatorial treatments showed a therapeutic activity and no toxicological effects in a murine topical infection model caused by antibiotic-resistant strains ( Garza-Cervantes et al, 2020b ). The above data therefore strongly suggest that combination therapies are a potential strategy in the development of new treatments against infectious diseases.…”