|Ph.D Student||Pokrovskaya Varvara|
|Subject||Hybrid Antibiotics: A Novel Approach to Delay Development|
of Bacterial Resistance
|Department||Department of Chemistry||Supervisor||Professor Timor Baasov|
|Full Thesis text|
The increasing emergence of antibiotic resistance in pathogenic bacteria to current antibiotics is a worldwide public health problem. One promising and newly emerging approach to fight resistant pathogens is combination therapy, where two or more different antibiotics are administered either as a mixture or cocktail. The underlying hypothesis is that treatments that interfere with multiple targets might delay the pathogen's ability to accumulate simultaneous mutations. The effect of a drug cocktail, however, does not always lead to a clear response and promising in vitro observations are not always translated into an improved therapy in clinical settings. In patients, drug concentrations fluctuate owing to variables such as different absorption and elimination rates. Alternatively, two different drugs covalently connected into one molecule, the "hybrid antibiotics", may solve these limitations and result in a powerful drug with the potential to reduce the rate of resistance development in pathogens.
The main goal of this project is the design, synthesis, and biological evaluation of novel hybrid antibiotics with the potential of overcoming the existing types of resistance to each partner drugs of the hybrid, and in parallel have a potential to delay the development of new resistance in pathogenic bacteria.
Based on this hypothesis, we designed and synthesized a library of new hybrid antibiotics, containing two commercially available drugs ciprofloxacin (fluoroquinolone) and neomycin B (aminoglycoside) connected via 1,2,3-triazole moiety.
The hybrid structures exhibited significant improvement in their antibacterial activity profiles against both Gram-negative and Gram-positive bacteria relative to that of neomycin B. Our compounds were especially potent against methicillin-resistant Staphylococcus aureus (MRSA), which is highly resistant to neomycin B. Furthermore, we have demonstrated that several hybrid structures are able to overcome most prevalent types of aminoglycoside resistance, and exhibit dual mode of action.
To evaluate the ability of hybrid antibiotics to slow the emergence of resistance we used a procedure of selective pressure, in which Gram-positive and Gram-negative bacteria were exposed to ciprofloxacin, neomycin B, their 1:1 mixture, and hybrid compound during 15 successive subcultures. The observed data demonstrated that the hybrids significantly delay resistance development in both Gram-negative and Gram-positive bacteria, than those either parent drugs or their 1:1 cocktail .
In summary, a series of hybrid compounds, containing a covalently linked fluoroquinolone and aminoglycoside with potent antibacterial activity and dual mode of action has been discovered. We also demonstrated a significant delay of resistance formation in bacteria to the treatment with hybrid compound.