New drug touted as potential big step in fighting resistant bacteria

A new antibiotic compound that was found in soil bacteria promises to be effective against a wide range of drug-resistant bacteria and may be difficult for mutating bacteria to evade, according to a report published today in Cell.

The drug, pseudouridimycin (PUM), inhibits RNA polymerase (RNAP), the enzyme that enables bacteria to make RNA, the authors say. In doing so, the agent uses a different mechanism and binding site than those used by the existing drug rifampin, which is also an RNAP inhibitor. The rate of spontaneous bacterial resistance against PUM is 90% lower than the resistance rate against rifampin, according to the report.

The researchers predicted that PUM could have a "transformative" effect on treatment of bacterial infections, similar to that of certain analogous drugs (nucleoside analog inhibitors) on the treatment of HIV/AIDS and hepatitis C.

But two antibiotics experts who were not involved in the study said PUM sounds promising but cautioned that it's too early to say it will have a major impact. In addition to safety and efficacy studies, they said, more work will be needed to determine the potential for resistance to PUM and how wide a range of bacteria it might cover, especially gram-negative bacteria.

Thousands of cultures screened

PUM was developed by a team of researchers from three Italian biomedical companies, Rutgers University, the University of Milan, and the University of Bonn.

They report that RNAP is the target of two existing classes of antibacterial drugs, rifamycins (including rifampin) and lipiarmycins (including fidaxomicin). In addition, bacterial RNAP is the target of a class of antibacterials now in clinical development, myxopyronins. But all three classes are subject to the emergence of spontaneous resistance, they say.

By screening a library of 3,000 bacterial and fungal culture extracts from soil samples, the researchers found two extracts that inhibited bacterial RNAP and met certain other criteria. Additional analysis showed that both extracts contained PUM as the active ingredient.

In further work, the team found that PUM selectively inhibited bacterial RNAP and bacterial growth in vitro and cleared Streptococcus pyogenes infections in mice, according to the report. The drug, they said, is active against both gram-positive and gram-negative bacteria, including strains that are resistant to many existing drug classes (rifamycins, beta-lactams, fluoroquinolones, tetracyclines, aminoglycosides, lincosamides, and several others).

The drug shows in vitro activity against 18 gram-positive bacterial species, mostly Streptococcus and Staphylococcus, and 2 gram-negative species, the report shows.

In other findings, the team said PUM shows no cross-resistance with rifampin (strains resistant to rifampin were not resistant to PUM), and the two drugs show "additive antibacterial activity when administered together."

The researchers determined that the rate of spontaneous S pyogenes resistance to PUM was one-tenth that against rifampin, which they said is explained by a much lower number of molecular sites where mutations can confer resistance to the new drug.

A novel mechanism

In a Rutgers press release, the authors said that PUM's use of a different binding site and mechanism to inhibit RNAP than that used by rifampin is the key to the new drug's advantages.

PUM serves as a nucleoside-analog inhibitor of bacterial RNAP, meaning that it mimics a nucleoside-triphosphate (NTP), the chemical building block that bacterial RNAP uses to make RNA, according to the release. The drug binds tightly to the NTP binding site on bacterial RNAP and thereby prevents NTPs from binding.

PUM is the first nucleoside-analog inhibitor that selectively inhibits bacterial RNA polymerase but not human RNA polymerases, the researchers said.

"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-analog inhibitor to inhibit bacterial RNA polymerase but not human RNA polymerases," senior author Richard H. Ebright, PhD, said in the release. He is a professor of chemistry and chemical biology and laboratory director at the Waksman Institute of Microbiology at 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," Ebright said.

He added that binding-site mutations that would block PUM from connecting to RNAP would be self-defeating, which helps explain the low rate of resistance emergence: "Alterations of the NTP binding site that disrupt binding of the new antibiotic also disrupt RNA polymerase activity, resulting in dead bacteria, rather than resistant bacteria."

Optimistic forecast

Another author, Stefano Donadio, CEO of NAICONS Srl., predicted that PUM could have an impact on antibacterial therapy like that of certain important drugs used to combat HIV-AIDS and hepatitis C.

"Nucleoside-analog inhibitors that selectively inhibit viral nucleotide polymerases have had transformative impact on the treatment of HIV-AIDS and hepatitis C," Donadio said. The AIDS drugs zidovudine, teneofovir, and lamivudine are nucleoside-analog inhibitors, as are the hepatitis-C drugs sofosbuvir (Solvadi) and ledipasvir/sofosbuvir (Harvoni), he noted.

"Nucleoside-analog inhibitors that selectively inhibit bacterial RNA polymerase could have a similarly transformative impact on the treatment of bacterial infections," he said.

"Our results provide a new class of antibiotic with activity against Gram-positive and Gram-negative bacteria in vitro and in vivo, no cross-resistance with current antibacterial drugs, and low rates of resistance emergence," the authors' report concludes. They said their discovery of PUM also suggests that, contrary to widespread belief, conventional microbial extract screening can still be a source of new antibacterial compounds.

Words of caution

As noted above, two other experts welcomed the news about PUM but were cautious about its possible impact.

"New agents with different mechanisms of action are a welcome addition and something everyone wants," said Keith Rodvold, PharmD, a professor of pharmacy practice at the University of Illinois at Chicago. "[But] it's a bit too early . . . to say this is going to be transformative."

Commenting on PUM's reported advantage over rifampin regarding resistance emergence, he said in an e-mail, "It's an improvement over rifampin and thus it might be a better choice for gram-positive pathogens, either by itself (maybe) or in combination. But if you are the one of ten patients to have spontaneous resistance, that's not good. More work is needed to further understand this potential advantage and when and/or what pathogens develop spontaneous resistance."

Rodvold also was circumspect about how broad a range of bacterial species the new drug might cover.

"These authors are showing activity against a limited number of pathogens to determine if this is going be a broad-spectrum antibiotic," he said. "The majority of pathogens belonged to the three major groups of gram-positive pathogens (eg, Staphylococcus, Streptococcus, Enterococcus) and only two gram-negative pathogens (eg, E coli, Moraxella catarrhalis). "Thus, more data with other pathogens are needed."

If PUM is like rifampin, "you would not anticipate lots of gram-negative pathogens or anaerobic pathogens will be covered," Rodvold added. "There are a lot of gram-positive drugs today, at least [intravenous ones]. We are currently in need of agents active against gram-negative pathogens, especially multidrug-resistant serious Gram-negative pathogens."

Similar views were expressed by John Rotschafer, PharmD, a professor in the Department of Experimental and Clinical Pharmacology at the University of Minnesota in Minneapolis.

"This is the kind of antibiotic we need" as it is "chemically and mechanistically unique," he commented. "Obviously more work will be required to establish safety and efficacy."

"If the drug makes it through clinical testing it will be useful but it would be better if it had activity against MDR [multidrug-resistant] gram-negatives such as Acinetobacter and Pseudomonas," he added. "Additional time will be required to establish that bacteria will not develop resistance."

Maffioli Si, Zhang Y, Degen D, et al. Antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase. Cell 2017 Jun 15 [Abstract]

See also:

Jun 15 Rutgers press release

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