Biology subjects

Makarova, O.

Publications and source records attributed to Makarova, O..

3 recordsLinked to original sources

bioRxiv2025

Ciprofloxacin-based ionic liquids demonstrate increased mutation frequency in Escherichia coli

In the last decade, development of active pharmaceutical ingredient ionic liquids (API-ILs) has been proposed as a prospective game-changing strategy to overcome multiple problems with conventional solid-state drugs. Formulation of antibiotics as API-ILs has been reported to improve physico-chemical parameters as well as possible synergistic effects overcoming antimicrobial resistance. What has not been assessed to date however are possible adverse effects of the API-ILs considering the potentially wide-scale application and the inevitable release to the environment, as is the case with antibiotics and other popular medications. In this study, API-ILs based on the antibiotic ciprofloxacin were synthesized and investigated in terms of their antimicrobial activity and influence on mutation frequency of Escherichia coli MG1655. This is the first report that by formulating of antibiotics as API-ILs, bacterial mutation frequencies can be significantly increased, while structurally similar chloride ILs alone do not have such an effect. The observed changes in mutation frequencies seem to be dependent on the structure of the respective counterion. As increased mutation frequencies can fuel adaptation and ultimately resistance development of bacteria, it is crucial to improve our understanding of how API-ILs can designed in a safer way.

microbiology↗

bioRxiv2019

Non-lethal oxidative stress boosts bacterial survival and evolvability under lethal exposure

Unicellular organisms have the prevalent challenge to survive under oxidative stress of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). ROS are present as by-products of photosynthesis and aerobic respiration. These reactive species are even employed by multicellular organisms as potent weapons against microbes. Although bacterial defences against lethal and sub-lethal oxidative stress have been studied in model bacteria, the role of fluctuating H2O2 concentrations remains unexplored. It is known that sub-lethal exposure of Escherichia coli to H2O2 results in enhanced survival upon subsequent exposure. Here we investigate the priming response to H2O2 at physiological concentrations. The basis and the duration of the response (memory) were also determined by time-lapse quantitative proteomics. We found that a low level of H2O2 induced several scavenging enzymes showing a long half-life, subsequently protecting cells from future exposure. We then asked if the phenotypic resistance against H2O2 alters the evolution of resistance against oxygen stress. Experimental evolution of H2O2 resistance revealed faster evolution and higher levels of resistance in primed cells. Several mutations were found to be associated with resistance in evolved populations affecting different loci but, counterintuitively, none of them was directly associated with scavenging systems. Our results have important implications for host colonisation and infections where microbes often encounter reactive oxygen species in gradients.

evolutionary biology↗

bioRxiv2017

Genomic signature of experimental adaptation of Staphylococcus aureus to a natural combination of insect antimicrobial peptides

Antimicrobial peptides are highly conserved immune effectors across the tree of life and are employed as combinations. In the beetle Tenebrio molitor, a defensin and a coleoptericin are highly expressed in vivo after inoculation with S. aureus. The defensin displays strong in vitro activity but no survival benefit in vivo. The coleoptericin provides a survival benefit in vivo, but no activity in vitro. To investigate this paradox we experimentally evolved S. aureus to increased resistance against the defensin and a combination of the defensin and coleoptericin. Genome re-sequencing showed that resistance was associated with mutations in either the ytr or nsa operons, in both AMP treatments. Strains with these mutations show longer lag phases, slower Vmax and nsa mutants reach lower final population sizes. Mutations in rpoB were showed a further increase in the lag phase in nsa mutants but not in ytr mutants. In contrast, final MICs do not segregate by mutation. All resistant lines display AMP but not antibiotic cross-resistance. Costly resistance against AMPs readily evolves for an individual AMP as well as a naturally occurring combination in vitro and provides broad protection against AMPs. Such non-specific resistance could result in strong selection on host immune systems that rely on cocktails of AMPs.

evolutionary biology↗