Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists take steps to make weak TB drugs strong again

19.01.2016

3-D structures could lead to more potent fluoroquinolones for the fight against other disease-causing bacteria too

Biophysicists have discovered why the bacteria that cause tuberculosis (TB) are naturally somewhat resistant to antibiotics known as fluoroquinolones. Their findings, based on mapping the detailed three-dimensional structure of the drugs interacting with an essential enzyme in the TB germ, also reveal why some TB drugs are more potent than others and suggest how drug developers can make fluoroquinolones more efficacious against mutations that make the lung disease drug resistant.


The drug moxifloxacin (green) interacts with internal regions of the gyrase enzyme (blues and pink) and broken DNA (orange and yellow), both from the bacterium that causes tuberculosis.

Credit: Tim Blower

Details of the research are reported in two papers to be published the week of Jan. 18 in the Proceedings of the National Academy of Sciences.

"Front-line treatments for TB are eroding rapidly as more cases of multidrug-resistant TB arise worldwide," says James Berger, Ph.D., professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine. "Our work helps show that we need not -- and indeed should not -- give up on fluoroquinolones, a longtime weapon in the fight against disease-causing bacteria in general. We've helped to identify several promising possibilities for developing new versions of these drugs that might even work against extensively drug-resistant TB."

Quinolones are a commonly used class of synthetic, broad-spectrum antibiotics that were first developed in the early 1960s. By the 1970s, more potent fluoroquinolone derivatives were made with the simple addition of a fluorine atom to the base molecule. All quinolones, Berger notes, kill bacteria in the same way, by gumming up the works of the enzyme gyrase, which alters the coiling of DNA by breaking its strands and then resealing them. Quinolones prevent resealing so that the bacterial DNA fall apart.

To better understand why some fluoroquinolones work better clinically than others, Berger and his research team used a high-powered imaging technique called X-ray crystallography to generate three-dimensional, atom-by-atom models of how TB's gyrase interacts with five different versions of the drugs, including a newly synthesized one, 8-methyl-moxifloxacin. Collaborators at Vanderbilt University also used a biochemical test to monitor how various derivatives of the drugs caused bacterial DNA to fall apart.

By viewing the "pocket" within gyrase where the drugs sit, the research team says it saw that the drugs have the potential to interact with the bacterial proteins at two different sites. At one of these sites, the researchers confirmed that a naturally swapped protein building block in TB's version of gyrase makes fluoroquinolones less effective against TB than against other bacterial infections. Surprisingly, none of the drugs latched on to the second site at all.

According to Berger, this means there is untapped potential to make fluoroquinolone derivatives that bind both sites and in that way increase the drugs' interactions with gyrase. And, because bacteria, including those that cause TB, might develop a mutation in one region but probably not both, Berger says they would be less likely to become resistant to a drug that strongly bound to both sites.

Most unexpectedly, though, the researchers say, they discovered that the more potent versions of the drugs did not interact strongly with either of the gyrase regions. Instead, their increased effectiveness was due to strong interactions with the broken DNA within the gyrase. When the researchers applied these drugs to the gyrase enzyme in solution and then rinsed it out, the more potent drugs remained stuck within the DNA-gyrase complex, while the weaker ones washed away.

"This result means the fluoroquinolones aren't working in the most straightforward way, and that's a challenge for drug developers," says Berger. "We have to rethink the chemistry of these drugs, but doing so will likely open up new avenues for improvements."

One such improvement, based on increased interactions with DNA, may already exist in the newly synthesized 8-methyl-moxifloxacin, created by University of Iowa chemist Robert Kerns. When Berger's team assessed the efficacy of the five fluoroquinolones against two common mutant forms of the TB gyrase, 8-methyl-moxifloxacin did better than the rest in test tube studies, suggesting that it may also perform better than related drugs against other drug-resistant bacteria.

"All together, these studies provide a wealth of information that drug companies can use to continue the development of fluoroquinolones," says Berger. "They hold a lot of promise for fighting drug resistance in bacteria that cause TB and many other diseases."

Though TB affects less than 10,000 people in the U.S., it is a leading cause of death worldwide, according to the World Health Organization, affecting 9.6 million people in 2014 and killing 1.5 million of them. Almost 500,000 of these cases are estimated to be multidrug resistant, and fluoroquinolones are under increasing investigation as a means to help counteract these resistant strains.

###

Other authors of the report include Tim Blower of the Johns Hopkins University School of Medicine (now an independent researcher at Durham University); Benjamin Williamson of the University of Iowa; and Katie Aldred and Neil Osheroff of Vanderbilt University School of Medicine.

This work was supported by funding through the European Molecular Biology Organization Long-Term Fellowship, the U.S. Department of Veterans Affairs' Merit Review Award (I01 Bx002198), the National Institute of Allergy and Infectious Diseases (R01 AI87671, the National Cancer Institute (R01 CA077373, T32 CA09582, ACB-12002), the National Institute of General Medical Sciences (R01 GM033944, AGM-12006, P41 GM103403), the National Center for Research Resources (S10 RR029205) and the U.S. Department of Energy (DE-AC02-06CH11357).

Media Contact

Catherine Gara
ckolf@jhmi.edu
443-287-2251

 @HopkinsMedicine

http://www.hopkinsmedicine.org 

Catherine Gara | EurekAlert!

Further reports about: DNA Johns Hopkins TB bacterial DNA drugs enzyme fluoroquinolones gyrase

More articles from Health and Medicine:

nachricht Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

nachricht The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>