Two promising avenues in the fight against antibiotic resistance

IBEC’s Bacterial infections: antimicrobial therapies group have published two papers offering new hope in the urgent search for antimicrobials.

“We desperately need antimicrobials,” says Eduard Torrents. “Antibiotic resistance is one of the greatest threats to human health today, and the time is fast approaching when routine procedures will be much more risky.”
Not only have some common infections or illnesses become resistant to the antibiotics usually used to treat them, a really pressing medical problem now is the rapid rise of ‘superbugs’ or multidrug-resistant bacteria, which are immune to almost all of the antibiotics that are currently available.

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Research groups like Eduard’s, supported in part by grants from the Obra Social “La Caixa”, are working on different ways to overcome bacterial resistance, such as developing new drugs against new targets, or interfering with the plasmids which confer resistance against existing antibiotics.

Publishing in ACS Omega with collaborators at the UB, the UAB and the University of Kwazulu-Natal in South Africa, the group reveals hydroxylamine derivatives to be promising new agents in the fight against drug-resistant pathogenic bacteria. The compounds – known as N-HA (N-substituted compounds of hydroxylamine, a hybrid of ammonia and water) – can be designed and synthesized with antibacterial activity. They can then act as ‘radical scavengers’ to inhibit ribonucleotide reductase (RNR), a bacterial enzyme essential for bacterial proliferation during infection, as it provides the building blocks for DNA synthesis and repair. This enzyme could be considered as a new antibacterial target to treat bacterial infections.

The work demonstrated the compounds’ low toxicity in the host and antimicrobial effect against a variety of bacteria, showing that they reduced the mass of an established biofilm – the environment in which bacteria can grow and adapt, creating the right conditions for infection – in disease-causing bacteria including Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli.

The second study, published in the high-impact Journal of Medicinal Chemistry with collaborators in Austria, NZ, Hungary, Serbia, Singapore and the Slovak Republic, describes another promising agent that could also offer anticancer properties.

Morpholine is known to demonstrate anticancer action – it is used in several commercial drugs – and the researchers synthesized morpholine-thiosemicarbazone hybrids and water-soluble copper(II) complexes that offered a marked antibacterial effect, inhibiting RNR via a process known as intracellular iron chellation. Such compounds with both anticancer and antibacterial properties offer the double benefit of simultaneously affecting the cancer malignancy while decreasing the risk of bacterial infections, which can often be the cause of death in immuno-compromised cancer patients.

“The emergence and increasing prevalence of bacterial strains that are resistant to available antibiotics demand the discovery of new therapeutic approaches like these,” says Eduard. “We need to do as much as we can now to postpone the day when clinical procedures like organ transplants, chemotherapy or the care of premature infants could become too dangerous to carry out.”

Laia Miret-Casals, Aida Baelo, Esther Julián, Josep Astola, Ariadna Lobo-Ruiz, Fernando Albericio, and Eduard Torrents (2018). Hydroxylamine Derivatives as a New Paradigm in the Search of Antibacterial Agents. ACS Omega 3 (12), pp 17057–17069

Kateryna Ohui, Eleonora Afanasenko, Felix Bacher, Rachel Lim Xue Ting, Ayesha Zafar, Nuria Blanco-Cabra, Eduard Torrents, Orsolya Domotor, Nora V. May, Denisa Darvasiova, Eva A Enyedy, Ana D. Popović-Bijelić, Johannes Reynisson, Peter Rapta, Maria Babak, Giorgia Pastorin, and Vladimir B. Arion (2018).Hydroxylamine Derivatives as a New Paradigm in the Search of Antibacterial Agents. New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action. J. Med. Chem., Just Accepted Manuscript