Antibiotic resistance remains one of the biggest public health challenges. While doctors are changing the way they use antibiotics to lower the risk of emerging resistance, new drugs are still needed to tackle tough-to-treat bacteria. But finding new therapeutics to kill off pathogenic bacteria has been difficult.
Scientists at the New York University (NYU) School of Medicine are pursuing a different strategy: They have uncovered an innate defense mechanism that protects bacteria from normally lethal doses of antibiotics, according to a new study published in Science.
By screening existing drug libraries, the researchers identified three candidates that could effectively cripple that bacterial defense system by inhibiting an enzyme called cystathionine gamma-lyase (CSE). The findings support the strategy of using a small-molecule potentiator to make bacteria more susceptible to antibiotics, the researchers suggested.
When exposed to antibiotics, some bacteria switch to a dormant state to survive in a process that’s mediated by the production of the molecule hydrogen sulfide (H2S). The NYU team previously showed that this mechanism is present in a wide variety of bacterial species, including Staphylococcus aureus and Pseudomonas aeruginosa, which have produced many multidrug-resistant strains. Previous studies have shown that genetic disruption of H2S could sensitize these pathogens to antibiotics and to the host immune response.
In the current study, the team first used mutants of S. aureus and P. aeruginosa to show that CSE is a critical source of H2S production. Deactivating CSE alone led to major reduction of H2S and was sufficient to sensitize the mutant strains to low doses of antibiotics, including gentamycin and ampicillin, the team found.
The researchers figured CSE could be targeted by drugs designed to make bacteria susceptible to antibiotics. But existing inhibitors of CSE showed very low activity against bacterial CSE. So the team went on to identify drugs that are more efficient at blocking bacterial CSE.
After identifying a possible bacterial CSE site that could be bound by drugs without causing toxic effects, the team screened about 3.2 million small molecules and selected three lead compounds, NL1, NL2 and NL3. In lab dishes, all three drugs showed a strong inhibitory effect on H2S production by both S. aureus and P. aeruginosa and enhanced the effect of antibiotics from different classes.
The team further tested NL1 in two mouse models of infection. In a mouse model of S. aureus sepsis, combining NL1 with gentamycin helped 50% of mice survive the challenge, whereas 90% of the control animals died. Neither NL1 nor gentamycin alone increased survival, the researchers reported.
In mice with lung infections caused by P. aeruginosa, the combo markedly decreased the bacterial burden, while no significant change was observed with solo NL1 or antibiotic.
Further analysis showed that NL1 significantly reduced the number of bacteria “persisters”—bugs that stopped multiplying and reduced energy use to survive antibiotic treatment—at a similar level as did genetic inactivation of CSE. It also disrupted the formation of biofilms, which are bacterial colonies that live in tough-to-reach matrices.
Most research aiming to combat the problem of antibiotic resistance focuses on developing new classes of antibiotics. Scientists at the University of Pennsylvania, for example, modified a peptide called mastoparan-L from the venom of Korean yellow-jacket wasp that can kill bacteria without causing harm to humans.
A team led by scientists at the University of California, Los Angeles (UCLA) recently took inspirations from proteins that P. aeruginosa produces to kill competing bacteria. UCLA spinoff Pylum Biosciences is designing new antibiotics based on those proteins, called R-type pyocins.
The NYU researchers behind the new study believe that suppressing bacterial H2S by inhibiting CSE could represent a new approach to bolstering the effect of existing antibiotics.
“Interfering with the H2S-based defenses represents a largely unexplored alternative to the traditional antibiotic discovery,” Evgeny Nudler, Ph.D., the study’s corresponding author, said in a statement. “Our results suggest that a new kind of small molecule potentiator can strengthen the effect of major classes of clinically important antibiotics.”
by Angus Liu
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