Scientists Hit Pay Dirt in Search for New Antibiotic

Italian soil sample yields pseudouridimycin

Scientists at Rutgers University–New Brunswick and the biotechnology company Naicons have discovered a new antibiotic that is effective against drug-resistant bacteria: pseudouridimycin. The new antibiotic is produced by a microbe found in a soil sample collected in Italy. The antibiotic killed a broad spectrum of drug-sensitive and drug-resistant bacteria in the lab and cured bacterial infections in mice, according to the investigators. Their findings were published in the journal Cell.

Pseudouridimycin inhibits bacterial RNA polymerase, the enzyme responsible for bacterial RNA synthesis, through a binding site and mechanism of action that differ from those of rifampin, an antibacterial drug that inhibits the enzyme. Because of these characteristics, pseudouridimycin exhibits no cross-resistance with rifampin; functions additively when co-administered with rifampin; and, most important, has a spontaneous resistance rate that is only one-tenth that of rifampin.

Pseudouridimycin functions as a nucleoside analogue inhibitor of bacterial RNA polymerase, meaning that it mimics a nucleoside-triphosphate (NTP)––the chemical “building block” that bacterial RNA polymerase uses to synthesize RNA. The new antibiotic occupies NTP binding sites on bacterial RNA polymerase, thereby preventing NTPs from binding to those sites.

According to the investigators, pseudouridimycin is the first nucleoside analogue inhibitor that selectively inhibits bacterial RNA polymerase but not human RNA polymerases.

“Because the NTP binding site of bacterial RNA polymerase has almost exactly the same structure and sequence as the NTP binding sites of human RNA polymerases, most researchers thought it would be impossible for a nucleoside-analogue inhibitor to inhibit bacterial RNA polymerase but not human RNA polymerases,” said co-lead investigator Richard H. Ebright, PhD, of Rutgers.

“But pseudouridimycin contains a side-chain that ‘reaches’ outside the NTP binding site and ‘touches’ an adjacent site that is present in bacterial RNA polymerase but not in human RNA polymerases, and as a result, it binds more tightly to bacterial RNA polymerase than to human RNA polymerases,” Dr. Ebright said.

The fact that pseudouridimycin functions as a nucleoside-analogue inhibitor explains the low rate of emergence of resistance to the compound, he remarked.

“Nucleoside analogue inhibitors that selectively inhibit viral nucleotide polymerases have had transformative impact on the treatment of HIV-AIDS and hepatitis C,” said co-lead investigator Stefano Donadio, PhD, CEO of Naicons. “The anti-AIDS drugs zidovudine [Retrovir, Viiv Healthcare], Videx [didanosine, Bristol-Myers Squibb], zalcitabine [Hivid, Roche], lamivudine [Epivir, Viiv Healthcare], and Viread [tenofovir disoproxil fumarate, Gilead] are nucleoside analogue inhibitors, and the anti-hepatitis C drugs Sovaldi [sofosbuvir, Gilead] and Harvoni [ledipasvir/sofosbuvir, Gilead] are nucleoside analogue inhibitors.”

“Nucleoside analogue inhibitors that selectively inhibit bacterial RNA polymerase could have a similarly transformative impact on the treatment of bacterial infections,” Dr. Donadio said. “The discovery also underscores the importance of natural products in providing new antibiotics. Microbes have had billions of years to develop ‘chemical weapons’ to kill other microbes.”

Source: EurekAlert; June 15, 2017.