Interview: The path to next-generation antibiotics Special

Posted Nov 7, 2017 by Tim Sandle
Dr. Marcos Pires is spearheading a novel approach to understanding bacterial cell wall changes in response to antibiotics that could be key to new drug design. We spoke with him to discover more about this approach.
H. pylori is a helix-shaped (classified as a curved rod  not spirochaete) Gram-negative bacterium ab...
H. pylori is a helix-shaped (classified as a curved rod, not spirochaete) Gram-negative bacterium about 3 μm long with a diameter of about 0.5 μm.
Institute for Systems Biology
Humans face the very real risk of a future without antibiotics. The implications of this are that life expectancy could fall due to people dying from diseases that are readily treatable today. This is unless new candidates drugs are discovered and put in place (see, for example, the Digital Journal article "What is being done about antibiotic resistance?") One target for new antimicrobials is the bacterial cell wall.
Bacterial cell walls, which are jacket-like structures that surround all known bacteria, have the potential to be a bacterium’s undoing. Cell walls hold the key to developing new drugs that target the wall for destruction. This could lead to designing next-generation antibiotics, and to help address the major societal concern of multi-drug antibiotic resistance.
This is central to the research of Dr. Marcos Pires, who is a biochemist at Lehigh University (Bethlehem , PA). His research has recently been recognized by the National Institutes of Health with a Maximizing Investigators' Research Award (MIRA).
To understand more about this alternative approach to antibiotic development, Digital Journal spoke with Dr. Pires.
Digital Journal: Hello Dr. Pires, thank you for the interview. What’s your take on the extent of the antibiotic resistance challenge?
Dr. Marcos Pires: My personal take is that it is one of the most important medical challenges we face right now. Given the difficulties in finding new antibiotic or antimicrobial strategies, it needs to be addressed now because by the time a true emergency situation comes up it may be another decade before a suitable antibiotic is discovered. The medical community is well aware of this. The problem is that the general public is much less so and that can distort the sense of urgency we should have.
There are many calls for immobilization of resources (including funding). Yet, this is not reflected in terms of federal funds to this cause. The funds dedicated to antimicrobial research is still a fraction of that going to other disease areas.
But instead of pinning on disease with the other, maybe we can think of the potential savings (current and future) in finding more suitable antibiotics. If that's the calculation, then funding can increase to the area of microbiology/antimicrobials without being disruptive to other disease areas.
Representative image of bacteria
Representative image of bacteria
DJ: Various causes are mentioned that affect the pace of resistance, from over-prescribing by physicians to adding antibiotics to animal feed. What’s your view of the key causes?
Dr. Pires: I think the field is in general agreement that any time a single antibiotic is prescribed (or disposed into the environment), then it serves as an opportunity for bacteria to learn and adapt. If we keep increasing these chances, then the result will be that resistance shows up sooner rather than later. Resistance to antibiotics is, of course, inevitable.
However, it does not mean that it should discourage from new discoveries. Quite the opposite. Given that resistance will always show up, it is imperative to maintain a discovery/development pace that matches that of drug resistance. We know from our experience in the 60s, 70s, and 80s that this is entirely possible.
Over-prescription by physicians will only improve when diagnostic tools allow doctors to differentiate between viral and bacterial infections with enough speed and precision as to not compromise a patient's health. This is why we need investment in several areas related to antibiotics. When it comes to antibiotics in animal feed, it has proven to be entirely unnecessary and something that should/can be addressed today.
DJ: You’re a biochemist by background. Has your research focus always been with bacteria?
Dr. Pires: I am actually an organic chemist by background. We only started focusing on bacteria about 4-5 years ago. But we are all in now. They are truly amazing given their apparent simplicity. The more you dig in, the more it becomes clear that they are exquisite life forms.
DJ: Your current research focuses on bacterial cell walls, examining for sites of vulnerability. How did you end up focusing on this aspect?
Dr. Pires: The chemical composition of the cell wall (made out of sugar and amino acids) are areas that I am very familiar with. I had extensive experience in making synthetic peptides to study biological system prior to coming to Lehigh. So the building blocks were familiar. I thought I could apply that knowledge to this very intriguing component of bacteria.
This key experiment shows the successful protection of a phage-sensitive bacterial strain against a ...
This key experiment shows the successful protection of a phage-sensitive bacterial strain against a virus. Top-right - bacteria growing in the absence of a virus; Top-left - holes in the culture caused by an infecting virus; Bottom - when equipped with specific CRISPR defense system components, the bacteria became resistant to the virus.
John van der Oost
DJ: You’re currently looking at syndetic cell wall fragments. What are these based on?
Dr. Pires: So we synthetically build mimics/analogs of cell walls in the lab in a way that still looks likes the building blocks that bacteria needs. If we do this successfully, then it allows us to decorate these building blocks with reporter handles and still trick the bacteria into thinking it’s one of its own building blocks. The end result is that we then get to find out how bacteria process these precursors to the cell wall.
DJ: How many iterations did it take to develop an optimal antimicrobial?
Dr. Pires: It depends on the organisms we are talking about. We had probably 3-4 iterations for Gram-positive bacteria but we still think there is work to be done. We recently got our first design to work well against Gram-negative bacteria. There are many potential redesigns and iterations. We do not think there is ever an optimal design and so we keep pushing to get better on each design.
DJ: How do the synthetic cell wall fragments work? Do they kill or inactivate bacteria?
Dr. Pires: We aim not to kill the bacteria. We are trying to trick bacteria to use our synthetic cell wall fragment in place of its own. The idea is to see how it processes these natural building blocks and looking for places that inform us about the biology of cell walls that was not known before.
DJ: Which types of bacteria have you tested out the fragments on? Have you had more success with some genus over others?
Dr. Pires: By this point, we have covered many, many types. Luckily, a lot of bacteria have some inherent promiscuity in how they accept our unnatural building blocks. Of course these are to different extent and some are a little bit more 'sloppy' than others. We have worked a lot with S. aureus due to the prevalence of MRSA infections and that the fact that drug resistance for these bacteria are usually related to cell wall biology.
DJ: Where have you published your research to date?
Dr. Pires: We have published in several journals including Angewandte Chemie, Plos ONE, ACS Chemical Biology, Biopolymers, Chemical Communications, Bioconjugate Chemistry.
DJ: What has been the response from microbiologists?
Dr. Pires: The response from microbiologists has been very encouraging. Most microbiologists that I talk to are excited about revealing new biology related to cell walls. The part that is most exciting is that we are building the cell wall fragments piece by piece.
By making these building blocks synthetically, we get to dictate exactly what it looks like so it becomes very versatile in terms of the questions we can ask and the systems we study.
Representative image of the bacterium Clostridium.
Representative image of the bacterium Clostridium.
Donna Rain
DJ: How far away are you from a commercial product?
Dr. Pires: Given how new the idea of immunotherapy against bacterial pathogens is, we are struggling to break through and get some of the more extensive testing done. The next phase of testing would require a larger investment because it would involve animal-testing. This is why we continue to redesign our agents to improve them.
The hope is that we finally find that one agent that excites a biologist enough that they test it in mice infected with bacterial infection. We need to find out how viable this new strategy really is.
Pires’s group continues to develop its unique approach focused on tricking bacteria into revealing where its cell wall is most vulnerable, and taking the lead in designing next-generation antibiotics that will circumvent drug resistance mechanisms.