New Research Further Confirms Inhibition of Flavomycin® on Resistance Gene Transfer

When looking at the mechanism of transfer, the location of the potential resistance genes plays a key role. Genes can be located on the bacterial chromosome or on plasmids: the difference in mobility of gene elements depends heavily on this, as those on the bacterial chromosome are in general a lot less mobile than genes located on plasmids. The underlying reason comes down to plasmid conjugation, or the sharing of plasmids between bacteria. As such, gene location has an impact on the potential relevance and risk of resistance transfer. 

Plasmids are cellular components present in certain microorganisms, such as bacteria, carrying genetic information. They are able to replicate independently of the chromosomes, yet coexist together, and as mentioned can be shared between bacteria via conjugative transfer. If these plasmids carry antimicrobial resistance genes, the ease of the conjugative transfer process will determine the potential rapid spread of antimicrobial resistance (Figure 1). As such, disrupting this conjugation results in a mitigating effect on AMR transfer.

Figure 1. Lateral transfer of antibiotic resistance via plasmids (adapted from Collingnon, 2002)

Flavomycin® can be used to disrupt this transfer, when observed in an animal production environment. The active component, flavophospholipol (FPL, also known as bambermycin), is an antimicrobial produced via fermentation. The molecule is used in certain markets as a feed additive for poultry, swine and cattle, usually supplemented to improve technical performance. Previous studies have shown that FPL restricts the cell wall synthesis of potential pathogens, as well as having an inhibitory effect on plasmid transfer between bacteria. As such, Flavomycin® has the potential to decrease the transfer of antimicrobial resistance genes between bacteria, making it an interesting option to combat AMR development on-farm.

The recent work of Kudo et al. (2019) went one step further, looking at the effect of FPL on the transfer of specific resistance genes, such as extended-spectrum β-lactamase (ESBL) and vanA genes. These are among the most important antimicrobial resistance loci known: ESBL for example can confer resistance to third generation cephalosporins, which are clinically important antimicrobials. As such, the importance of these genes in the broader AMR context is clear, as is the mitigation of their transference.

Figure 2. Effect of different concentrations of FPL on the first round conjugative transfer frequency in different E. coli donor strains (Dc1, Dc2 and Dc3), showing a clear decrease in frequency with increasing levels of FPL (Kudo et al., 2019)

The researchers concluded that FPL reduced the frequency of conjugative plasmid transfer harbouring these genes in a concentration-dependent manner (Figures 2 and 3). For some strains, this activity was partially explained by the ability of FPL to eliminate plasmids within the cells themselves (plasmid curing). 

Figure 3. Single linear regression analysis of the relationship between % curing efficiencies and different concentrations of FPL in E. coli donor strains (Dc1, Dc2 and Dc3), showing a dose-response relationship between the concentration of FPL and % curing efficiency (Kudo et al., 2019)

These results suggest that the use of FPL as a feed additive might decrease the dissemination of relevant resistance genes in animal production. As such, Flavomycin® is not only interesting in terms of improving production, but also fits into the wider category of food safety and AMR mitigation.

References are available upon request.