UNM Researchers Tackle Antibiotic Resistance with HPC

By Nicole Hemsoth

December 16, 2005

Since its discovery more than 70 years ago by Alexander Fleming, penicillin and its analogs have been at the forefront of the fight against bacterial infections. These molecules share a common ring motif called beta-lactam, thus the name beta-lactam antibiotics. They operate by forming a covalent adduct with membrane-bound bacterial transpeptidases, which are also known as penicillin-binding proteins, involved in the biosynthesis of cell walls. These mechanism-based inhibitors prevent the construction of the bacterial cell wall and lead eventually to cell lysis and death.

In the last twenty years, the efficacy of these antibiotics has been overshadowed by the emergence of drug-resistant bacterial strains resulting from their evolutionary responses to widespread overuse and abuse of antibiotics in clinical and agricultural settings. The problem has escalated to a crisis level, posing a serious public-health and economic challenge to modern society. There are many ways that bacteria adopt to resist the antibiotics. The most common and effective strategy is through a bacterial enzyme called beta-lactamase, which inactivates beta-lactam antibiotics by breaking the C-N bond in the lactam ring with a water molecule (hydrolysis). Such a reaction is typically very slow in water solution, but can be greatly accelerated by the enzyme. So, the understanding of how beta-lactamase catalyzes the hydrolysis of beta-lactam antibiotics would help us to design effective drugs to inhibit its activity. In fact, the co-administration of antibiotics and beta-lactamase inhibitors is now a common clinical practice.

Assistant Research Professor D. Xu and Professor H. Guo in the Department of Chemistry at the University of New Mexico (UNM) are using sophisticated computational approaches to understand the catalytic mechanism of a unique class of beta-lactamases. The so-called Class B2 beta-lactamases possess a zinc ion in its active site, which helps to accelerate the hydrolysis of a beta-lactam antibiotic molecule that docks at the active site. Although the Class B2 beta-lactamases are still rare in the clinical setting, an alarming trend in recent years points to a rapid spread of these metallo-enzymes in pathogenic micro-organisms by plasmid-mediated gene exchanges. Their broad substrate spectra and the absence of clinically useful inhibitors render them a dangerous threat to the relatively small arsenal of beta-lactam antibiotics.

A key step in designing inhibitors is to understand the mode of binding for the antibiotic molecule in the enzyme active site and the structure of the transition state in the slowest step of the catalysis. Unfortunately, the enzyme has so far resisted to yield its secret. This is because the enzyme-catalyzed hydrolysis reaction is so fast that it is not amenable to any existing experimental technique in structure determination. The lack of substrate analogs (inhibitors) for Class B2 beta-lactamases renders it very difficult to determine how the antibiotic molecule binds with the enzyme. Computational approaches can thus be very helpful to unravel the structure and reaction kinetics of the antibiotic-enzyme complex.

In a recent publication in Journal of Medicinal Chemistry, the two UNM researchers reported a computational study of the antibiotic binding dynamics of a third generation beta-lactam antibiotic molecule (biapenem) to a beta-lactamase (CphA) from the bacterium A. hydrophila. Using a state-of-the-art quantum mechanical/molecular mechanical (QM/MM) method, the UNM study identified a unique binding mode that sheds valuable light on the catalytic mechanism of the beta-lactamase. This binding model is unique in that it is consistent with a recently published structure of enzyme-intermediate complex.

It was determined that the antibiotic, biapenem, is engaged in direct metal binding with the zinc co-factor in the enzyme through its 3-carboxylate oxygen. It is further anchored by several hydrogen bonds between the substrate and active-site residues, particularly those made possible by conformational changes of Asn233. An active-site water is poised to attack the carbonyl carbon in the beta-lactam ring of the antibiotic molecule, with the help of either a Histidine or Aspartate residue serving as the general base. Work to elucidate the detailed catalytic mechanism using the QM/MM approach is underway in their laboratory, which is expected to provide helpful guidance to the designing of mechanism-based inhibitors that mimic the transition state structure.

Part of the UNM work was carried out on a recently purchased high performance shared-memory computer — IBM p570 — with 16 Power 5 chips and 256 GB of memory. This new addition to UNM's HPC center was made possible by a Major Research Instrumentation grant from the National Science Foundation. As the Principal Investigator of the NSF grant, Professor Guo is very excited about the prospect of scientific computing at UNM. Apart from the beta-lactamase project, the Guo group is also investigating a number of important enzymatic reactions, such as proton transfer, phosphoryl-transfer, hydrolysis, and arginine modification. The insights provided by these computational studies will help us to understand catalytic principles in general and to design new drugs that block the enzyme catalysis when needed.

This article originally appeared in the December 2005 HPC@UNM Newsletter. For more information visit http://www.hpc.unm.edu/.

Subscribe to HPCwire's Weekly Update!

Be the most informed person in the room! Stay ahead of the tech trends with industy updates delivered to you every week!

IBM, D-Wave Report Quantum Computing Advances

May 18, 2017

IBM said this week it has built and tested a pair of quantum computing processors, including a prototype of a commercial version. That progress follows an an Read more…

By George Leopold

PRACEdays 2017 Wraps Up in Barcelona

May 18, 2017

Barcelona has been absolutely lovely; the weather, the food, the people. I am, sadly, finishing my last day at PRACEdays 2017 with two sessions: an in-depth loo Read more…

By Kim McMahon

US, Europe, Japan Deepen Research Computing Partnership

May 18, 2017

On May 17, 2017, a ceremony was held during the PRACEdays 2017 conference in Barcelona to announce the memorandum of understanding (MOU) between PRACE in Europe Read more…

By Tiffany Trader

NSF, IARPA, and SRC Push into “Semiconductor Synthetic Biology” Computing

May 18, 2017

Research into how biological systems might be fashioned into computational technology has a long history with various DNA-based computing approaches explored. N Read more…

By John Russell

HPE Extreme Performance Solutions

Supercomputers Helping Researchers Predict Climate Change

Today’s weather and climate scientists are tasked with analyzing a massive tidal wave of data in order to better understand and predict significant changes affecting the climate. Read more…

DOE’s HPC4Mfg Leads to Paper Manufacturing Improvement

May 17, 2017

Papermaking ranks third behind only petroleum refining and chemical production in terms of energy consumption. Recently, simulations made possible by the U.S. D Read more…

By John Russell

PRACEdays 2017: The start of a beautiful week in Barcelona

May 17, 2017

Touching down in Barcelona on Saturday afternoon, it was warm, sunny, and oh so Spanish. I was greeted at my hotel with a glass of Cava to sip and treated to a Read more…

By Kim McMahon

NSF Issues $60M RFP for “Towards a Leadership-Class” System

May 16, 2017

In case you missed it, the National Science Foundation issued the request for proposals (RFP) for the next ‘Towards a Leadership-Class Computing Facility – Read more…

By John Russell

Cray Offers Supercomputing as a Service, Targets Biotechs First

May 16, 2017

Leading supercomputer vendor Cray and datacenter/cloud provider the Markley Group today announced plans to jointly deliver supercomputing as a service. The init Read more…

By John Russell

Cray Offers Supercomputing as a Service, Targets Biotechs First

May 16, 2017

Leading supercomputer vendor Cray and datacenter/cloud provider the Markley Group today announced plans to jointly deliver supercomputing as a service. The init Read more…

By John Russell

HPE’s Memory-centric The Machine Coming into View, Opens ARMs to 3rd-party Developers

May 16, 2017

Announced three years ago, HPE’s The Machine is said to be the largest R&D program in the venerable company’s history, one that could be progressing tow Read more…

By Doug Black

What’s Up with Hyperion as It Transitions From IDC?

May 15, 2017

If you’re wondering what’s happening with Hyperion Research – formerly the IDC HPC group – apparently you are not alone, says Steve Conway, now senior V Read more…

By John Russell

Nvidia’s Mammoth Volta GPU Aims High for AI, HPC

May 10, 2017

At Nvidia's GPU Technology Conference (GTC17) in San Jose, Calif., this morning, CEO Jensen Huang announced the company's much-anticipated Volta architecture a Read more…

By Tiffany Trader

HPE Launches Servers, Services, and Collaboration at GTC

May 10, 2017

Hewlett Packard Enterprise (HPE) today launched a new liquid cooled GPU-driven Apollo platform based on SGI ICE architecture, a new collaboration with NVIDIA, a Read more…

By John Russell

IBM PowerAI Tools Aim to Ease Deep Learning Data Prep, Shorten Training 

May 10, 2017

A new set of GPU-powered AI software announced by IBM today brings automation to many of the tedious, time consuming and complex aspects of AI project on-rampin Read more…

By Doug Black

Bright Computing 8.0 Adds Azure, Expands Machine Learning Support

May 9, 2017

Bright Computing, long a prominent provider of cluster management tools for HPC, today released version 8.0 of Bright Cluster Manager and Bright OpenStack. The Read more…

By John Russell

Microsoft Azure Will Debut Pascal GPU Instances This Year

May 8, 2017

As Nvidia's GPU Technology Conference gets underway in San Jose, Calif., Microsoft today revealed plans to add Pascal-generation GPU horsepower to its Azure clo Read more…

By Tiffany Trader

Quantum Bits: D-Wave and VW; Google Quantum Lab; IBM Expands Access

March 21, 2017

For a technology that’s usually characterized as far off and in a distant galaxy, quantum computing has been steadily picking up steam. Just how close real-wo Read more…

By John Russell

Google Pulls Back the Covers on Its First Machine Learning Chip

April 6, 2017

This week Google released a report detailing the design and performance characteristics of the Tensor Processing Unit (TPU), its custom ASIC for the inference Read more…

By Tiffany Trader

Trump Budget Targets NIH, DOE, and EPA; No Mention of NSF

March 16, 2017

President Trump’s proposed U.S. fiscal 2018 budget issued today sharply cuts science spending while bolstering military spending as he promised during the cam Read more…

By John Russell

HPC Compiler Company PathScale Seeks Life Raft

March 23, 2017

HPCwire has learned that HPC compiler company PathScale has fallen on difficult times and is asking the community for help or actively seeking a buyer for its a Read more…

By Tiffany Trader

CPU-based Visualization Positions for Exascale Supercomputing

March 16, 2017

Since our first formal product releases of OSPRay and OpenSWR libraries in 2016, CPU-based Software Defined Visualization (SDVis) has achieved wide-spread adopt Read more…

By Jim Jeffers, Principal Engineer and Engineering Leader, Intel

Nvidia Responds to Google TPU Benchmarking

April 10, 2017

Last week, Google reported that its custom ASIC Tensor Processing Unit (TPU) was 15-30x faster for inferencing workloads than Nvidia's K80 GPU (see our coverage Read more…

By Tiffany Trader

TSUBAME3.0 Points to Future HPE Pascal-NVLink-OPA Server

February 17, 2017

Since our initial coverage of the TSUBAME3.0 supercomputer yesterday, more details have come to light on this innovative project. Of particular interest is a ne Read more…

By Tiffany Trader

Facebook Open Sources Caffe2; Nvidia, Intel Rush to Optimize

April 18, 2017

From its F8 developer conference in San Jose, Calif., today, Facebook announced Caffe2, a new open-source, cross-platform framework for deep learning. Caffe2 is Read more…

By Tiffany Trader

Leading Solution Providers

Tokyo Tech’s TSUBAME3.0 Will Be First HPE-SGI Super

February 16, 2017

In a press event Friday afternoon local time in Japan, Tokyo Institute of Technology (Tokyo Tech) announced its plans for the TSUBAME3.0 supercomputer, which w Read more…

By Tiffany Trader

Nvidia’s Mammoth Volta GPU Aims High for AI, HPC

May 10, 2017

At Nvidia's GPU Technology Conference (GTC17) in San Jose, Calif., this morning, CEO Jensen Huang announced the company's much-anticipated Volta architecture a Read more…

By Tiffany Trader

Is Liquid Cooling Ready to Go Mainstream?

February 13, 2017

Lost in the frenzy of SC16 was a substantial rise in the number of vendors showing server oriented liquid cooling technologies. Three decades ago liquid cooling Read more…

By Steve Campbell

MIT Mathematician Spins Up 220,000-Core Google Compute Cluster

April 21, 2017

On Thursday, Google announced that MIT math professor and computational number theorist Andrew V. Sutherland had set a record for the largest Google Compute Eng Read more…

By Tiffany Trader

IBM Wants to be “Red Hat” of Deep Learning

January 26, 2017

IBM today announced the addition of TensorFlow and Chainer deep learning frameworks to its PowerAI suite of deep learning tools, which already includes popular Read more…

By John Russell

HPC Startup Advances Auto-Parallelization’s Promise

January 23, 2017

The shift from single core to multicore hardware has made finding parallelism in codes more important than ever, but that hasn't made the task of parallel progr Read more…

By Tiffany Trader

HPC Technique Propels Deep Learning at Scale

February 21, 2017

Researchers from Baidu's Silicon Valley AI Lab (SVAIL) have adapted a well-known HPC communication technique to boost the speed and scale of their neural networ Read more…

By Tiffany Trader

US Supercomputing Leaders Tackle the China Question

March 15, 2017

As China continues to prove its supercomputing mettle via the Top500 list and the forward march of its ambitious plans to stand up an exascale machine by 2020, Read more…

By Tiffany Trader

  • arrow
  • Click Here for More Headlines
  • arrow
Share This