By adding amino acids to the molecule of tobramycin, researchers created a new antibiotic drug molecule, pentobra, which can punch holes in persister cell membranes to get inside to kill the bacteria.
The pace at which bacteria are developing resistance to antibiotics presents an urgent global-health concern. But now, an interdisciplinary team of scientists from UCLA’s California NanoSystems Institute has developed a method to re-engineer antibiotics to enhance their activity against key cells that are responsible for making bacteria resistant to new drugs.
The cells, known as persisters, slow down their metabolism and shut down their mechanisms for taking in molecules, preventing normal antibiotics from penetrating them to kill the bug. To overcome this resistance, the team, led by Gerard C.L. Wong, PhD, professor in the UCLA Department of Chemistry and Biochemistry and the Department of Bioengineering, and Andrea M. Kasko, PhD, associate professor of bioengineering, developed a method analogous to taking an ordinary car and adding high-performance parts to make a fast-and-furious street racer.
“We’re in an unsustainable race with bacteria,” Dr. Wong says. “It takes upward of $100 million to develop one antibiotic drug, and bacteria develop resistance to it within two years. This reality brought us to the idea of taking an existing antibiotic wand and renovating it to give it a new and complementary antimicrobial ability, while preserving its original ability, to make a better drug overall.”
The team began with the antibiotic tobramycin, to which many persisters are resistant. By adding amino acids to the molecule of tobramycin, they created a new antibiotic drug molecule, pentobra, which is able to punch holes in the membranes of persister cells to get inside to kill the bacteria. “Pentobra can punch enough holes in the cell membrane to kill the cell, but that may not be the most efficient way to kill a bug,” Dr. Wong says. “This antibiotic also messes up the bacteria’s ability to grow by preventing them from making more bacterial proteins.”
The synergistic one-two punch is “what makes this antibiotic so powerful and why pentobra can kill persister-cell strains 10,000-to-1-million times better than tobramycin,” Dr. Wong says.
This revolutionary process can be used to renovate other existing antibiotics to resurrect their activity against resistant bacteria and to enhance their potency. The new approach also can potentially be used to improve many new antibiotics being developed. “If someone has a drug they think has potential, with our method, they may be able to make it even more potent,” Dr. Kasko says.
“Engineering Persister-Specific Antibiotics with Synergistic Antimicrobial Functions,” ACS Nano, August 18, 2014