Acidic amino acids, aspartic acid (Asp) and glutamic acid (Glu) can enhance the solubility of many poorly soluble drugs including ciprofloxacin (Cip). One of the mechanisms of resistance within a biofilm is retardation of drug diffusion due to poor penetration across the matrix. To overcome this challenge, this work set to investigate novel counter ion approach with acidic amino acids, which we hypothesised will disrupt the biofilm matrix as well as simultaneously improve drug effectiveness. The anti-biofilm activity of D-Asp and D-Glu was studied on Staphylococcus aureus biofilms. Synergistic effect of combining D-amino acids with Cip was also investigated as a strategy to overcome anti-microbial resistance in these biofilms. Interestingly at equimolar combinations, D-Asp and D-Glu were able to significantly disperse (at 20 mM and 40 mM) established biofilms and inhibit (at 10 mM, 20 mM and 40 mM) new biofilm formation in the absence of an antibiotic. Moreover, our study confirmed L-amino acids also exhibit anti-biofilm activity. The synergistic effect of acidic amino acids with Cip was observed at lower concentration ranges (<40 mM amino acids and <90.54 µM, respectively), which resulted in 96.89% (inhibition) and 97.60% (dispersal) reduction in CFU with exposure to 40 mM amino acids. Confocal imaging indicated that the amino acids disrupt the honeycomb-like extracellular DNA (eDNA) meshwork whilst also preventing its formation.
Antimicrobial resistance (AMR) is emerging as a global threat to public health. One of the strategies employed to combat AMR is the use of adjuvants which act to enhance or reinstate antimicrobial activity by inhibiting resistance mechanisms. However, these adjuvants are themselves not immune to selecting resistant phenotypes. Thus, there is a need to utilise mechanisms which are either less likely to or unable to trigger resistance. One commonly employed mechanism of resistance by microorganisms is to prevent antimicrobial uptake or efflux the antibiotic which manages to permeate its membrane. Here we propose amino acids as antimicrobial adjuvants that may be utilizing alternate mechanisms to fight AMR. We used a modified ethidium bromide (EtBr) efflux assay to determine its efflux in the presence of ciprofloxacin within Staphylococcus aureus (NCTC 8325) and Pseudomonas aeruginosa (PAO1). In this study, aspartic acid and glutamic acid were found to inhibit growth of both bacterial species. Moreover, a reduced production of toxic pigments, pyocyanin and pyoverdine by P. aeruginosa was also observed. As evident from similar findings with tetracycline, these adjuvants, may be a way forward towards tackling antimicrobial resistance.
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