Advances in antimicrobial research February 2019 Cover story

Advances in antimicrobial research February 2019 Cover story

Overview

  • Post By : Kumar Jeetendra
  • Source: Microbioz India : February 2019 edition
  • Date: 25 March, 2019

Following the introduction of penicillin in the 1940s antimicrobial medicines have become an essential tool for combatting microbial infections in humans and animals. Antimicrobials are necessary for preventing infections and reducing the risk of potentially life threatening complications during surgery. However, the act of using antimicrobials fuels antimicrobial resistance. Each time a single antibiotic is prescribed (or disposed into the environment), then it serves as an opportunity for bacteria to learn and adapt. Hence, resistance to antibiotics isinevitable. The current issue is with the rate at which this happens.

In the last two decades, the rate at which bacteria are becoming resistant to current antibiotic treatments has substantially increased. Antibiotic resistance is a form of drug resistance whereby some sub-populations of a microorganism are able to survive after exposure to one or more antibiotics. One of the triggers for this is due to the overuse of use medicines, as arises from mis-prescribing or the use of antibiotics with farm animals.

This trend is threatening the ability of medical staff to carry out routine operations or transplants in the future, or for medics to treat patients. This has been compounded not only by microorganisms that are resistant to one antimicrobial or another, but due to the rise of multi-drug resistant microorganisms (the so-termed ‘super bugs’). Prominent examples include MRSA (methicillin-resistant Staphylococcus aureus), VISA (vancomycin-intermediate S. aureus), VRSA (vancomycin-resistant S. aureus), ESBL (Extended spectrum beta-lactamase), VRE (vancomycin-resistant Enterococcus) and MRAB (multidrug-resistant Acinetobacter baumannii) (1).

An example of the problem of antimicrobial resistance is with the disease gonorrhoea, where rates of antimicrobial resistant strains of Neisseria gonorrhoeaehave been increasing, according to the World Health Organization (2). The United Nations health body warns that, as things stand today, if someone contracts gonorrhea, it is now much harder to treat, and in some cases treatment is impossible. This is because the sexually transmitted infection is rapidly developing resistance to all antibiotics. An estimated 78 million people are infected with gonorrhea each year, according to the U.S. Centers for Disease Control and Prevention (3). As well as discomfort the disease can cause infertility.

These issues have placed renewed focus on the need to develop new antimicrobials and new methods for treating patients with bacterial infections. The current state of the antibiotic market is troubling. Funding is scarce, big pharmaceutical companies are shuttering their research and development programs and much of the burden is being left to smaller companies with fewer resources, or the initiatives are coming from government-backed programmes in academia. Despite the less-than-ideal rate of innovation, there are some interesting strands of work emerging (4). This articles surveys some of the more recent developments.

Seeking new classes of antibiotics

In order to combat multi-drug resistance there is a pressing need to discover new classes of antimicrobials, including antibiotics. New candidates are emerging, although the research and development timelines will be lengthy and no new antimicrobial classes have been clinically approved in over three decades (5). A promising new class of antibiotics are odilorhabdins. These chemicals are promising for two reasons. Firstly, the compound has a distinct way of killing bacteria. Secondly, the source of the compound is unusual. This strengthens the podetial use, should the compound be commercialized, for tackling hard-to-treat bacterial infections (6).

As with many clinically useful antibiotics, odilorhabdins work by targeting the ribosome. However, odilorhabdins are unique because they bind to a place on the ribosome that has never been used by other known antibiotics.With this mechanism, when odilorhabdins are introduced to the bacterial cells they impact the reading ability of the ribosome and this causes the ribosome to make mistakes as it creates new proteins. Trials to date have shown good effectiveness of the antibiotic against carbapenem-resistant Enterobacteriacae, a group that contains several antimicrobial resistant members

In terms of the atypical source for the chemicals, they are produced by symbiotic bacteria found only in soil-dwelling nematode worms. The bacteria colonize insects for food, and they also provide a degree or protection from bacteria that are pathogenic to the worms. This protection is through secreting the antibiotic.As part of the process to find the new antibiotic, microbiologists screened 80 cultured strains of the bacteria for antimicrobial activity. Next, they isolated the active compounds, and proceeded to study their chemical structures. From this the researchers engineered more potent derivatives.

In a separate research line, U.S scientists have discovered a new antibiotic family discovered from dirt (from samples of soil).The discovery of the new compounds comes from Rockefeller University and it is hoped that drug products can be developed that will combat the most resistant bacteria (which cannot be treated with most existing antimicrobials; bacteria that pose a risk to human health.Initial tests indicate that the compounds, termed malacidins (or metagenomic acidic lipopeptide antibiotic-cidins), can destroy several types of bacteria, including those resistant to most existing antibiotics, including MRSA.

Malacidins are a class of chemicals made by non-pathogenic bacteria found in soil that can kill some Gram-positive type bacteria; included within this morphological group are some of the organisms that cause the more serious diseases, including those associated with hospital acquired infections.The class malacidins are forms of macrocycle lipopeptides. They become active against certain bacteria after they bind to calcium. Following this the calcium-bound molecule then appears binds to lipid II, which a bacterial cell wall precursor molecule. This then triggers bacterial cell destruction, killing the target bacterium (7).


A different area of focus is with insects. From an analysis of bacteria from more than 1,400 insects collected across North and South America, an international team of researchers have found hat the microorganisms carried by an array of insectshave the potential to be more effective than soil bacteria in combating antibiotic-resistant pathogens.The types of organisms screened for form part of defensive symbioses, where bacterial symbionts produce antimicrobials to protect against opportunistic and specialized pathogens. Research shows that distinct evolutionary lineages of Streptomyces from insect microbiomes has the postnasal for a source of new antimicrobials, as assessed through large-scale isolations, bioactivity assays, genomics, metabolomics, and in vivo infection models (8).

Updating existing classes of antibiotics

While extensions to existing classes of antibiotics will not be as effective as finding new classes of antibiotics, the expansion of antibiotic portfolios provides a means to tackle some concerns of drug resistance. As an example of this process, two new tetracyclines, omadacycline and erava­cycline, have recently been approved by the U.S. Food and Drug Administration(FDA). Similar to tigecycline, these agents were designed to have activity specifically against tetracycline-resistant organisms.

Omadacycline is a broad-spectrum agent active against gram-positive organisms, including vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus; Gram-negative organisms, including some extend­ed-spectrum b-lactamase (ESBL)-producing Enterobacteriaceae and Acinetobacter baumannii; atypicals; and anaerobes. In terms of clinical use, omadacycline presents an alternative agent for patients with multiple antimicrobial allergies that limit thera­peutic options and as an alternative to fluoroquinolones (9).

Researching pathogens for weaknesses

There remains much to understand with bacteria and with pathogenic organisms specifically. Bacterial cell wallshave, according to many researchers, 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. One way to examine for bacterial cell weak spots is to synthetically build analogues of cell walls in laboratory in a way that looklikes the building blocks that bacteria needs. If this is undertaken successfully, then it allows microbiologists to decorate these building blocks with reporter handles and trick the bacteria into thinking it’s one of its own building blocks. The end result is that microbiologists then get to find out how bacteria process these precursors to the cell wall. The aim is not to kill the bacteria but rather to trick bacteria to use a synthetic cell wall fragment in place of its own. The idea is to see how it processes these natural building blocks and to look for places that inform microbiologists about the biology of cell walls that was not known before (10).

From a different perspective, researchers have been exploring the use of a "molecular pencil sharpener." This is a device that uses chemicals to generate a "warhead" of proteins that increase in toxicity once “sharpened”. The research has focused on killing Escherichia coli cells. This is based on microcin B17. Microcins are a family of toxins produced by the class of bacteria called Enterobacteriaceae and they inhibit phylogenetically related species. This is part of a natural competitive mechanism.Microcins are composed of a relatively few peptides. What is interesting about this new antibiotic (B17) is that prior to being activated, the compound is situated and embedded in a structure called a prodrug. The researchers, from Rutgers University–New Brunswick, describe this as much-like the core of an unsharpened “molecular pencil.”Microcin B17 targets DNA gyrase, the bacterial enzyme that introduces supercoils into DNA, although the site and mode of action is unclear.To give the antibiotic its potency and bacterial killing properties, the researchers have discovered a so-termed “molecular pencil sharpener”. This molecular device cuts away and the outer coating of microcin B17 to release the powerful antibiotic. This discovery potentially opens the door towards developing new antibacterial agents and drugs to fight toxins (11).

Accelerating antibiotics by printing medicines

An obstacle with the development of new antibiotics is the time involved. To help to address this, global technology company Hewlett Packard (HP) is to work with the U.S. Centers for Disease Control and Prevention to help to accelerate the testing of new antibiotics. The pilot programme will use HP proprietary technology to “print” test plates. When testing is not available, new drugs can be either over-utilized (which can lead to antimicrobial resistance) or be underutilized (where patients do not get the medicines they need).

For the study, the CDC will use new HP D300e Digital Dispenser BioPrinters at four of its laboratories, which form the Antibiotic Resistance Lab Network. This is to develop antimicrobial susceptibility test methods so that new candidate antimicrobials can be screened.The technology will enable regional laboratories to conduct fast susceptibility testing for various U.S. health departments and hospitals.The HP printer accelerates the availability of test kits at the reginal level through “printing” the test plates required for analysts to evaluate suitable antibiotics within a few minutes. The device dispenses volumes, ranging from picoliters to microliters, to enable speedier and more accurate dispensing of small molecules to assist with drug discovery and for performing antimicrobial susceptibility testing for new drugs (12).

Resupposing old medicines

A new initiative from University of Leeds sets to review previously discarded medicinal products in order to assess these drugs for potential antimicrobial properties.The review aims to see if chemicals discarded in the past can be ‘resupposed’ to create new antimicrobial compounds. Amongst the thousands antibiotics discovered to date, only a handful have been brought into clinical use. It is likely there is be a wealth of compounds stored in the world’s laboratories with untapped potential.

So far, the researchers have identified one compound, first proposed in the 1940s, as a contender for a new class of antibiotic medicine. This is a family of chemicals called actinorhodins. From this family, one specific compound (y-ACT) is worthy of further study. Initial studies have shown that y-ACT is effective against the so-termed ESKAPE group of pathogens (bacteria that can ‘escape’ the action of conventional antimicrobial drugs). Bacteria in this grouping include hospital acquired infectious agents like Staphylococcus aureus and Klebsiella pneumoniae(13). A second chemical called pentyl pantothenamide, first assessed in the 1970s, also shows promise for the next stage of research (14).

Application of oxygen treatment

Scientists have turned to an unusual source in order to tackle the problem of pathogenic bacteria – oxygen. This is in relation to MRSA, which is associated with hospital derived infections.The process utilizes a photosensitizer, oxygen, and light of appropriate wavelength.The new method makes use of light to activate oxygen, through the use of photosensitizers (dye molecules) that become excited when illuminated with light. This leads to the death of bacteria, including the means to destroy antibiotic-resistant bacteria. With the method, the photosensitizers (a molecule that produces a chemical change in another molecule in a photochemical process) convert oxygen into reactive oxygen species that attack the bacteria. Reactive oxygen species can trigger significant damage to cell structures. This process was improved by the researchers through the inclusion of metal nanoparticles, which promote the generation of more reactive oxygen species and direct the process of cell killing to specific sites on the bacterial cell wall. The application of red light further boosts the efficiency of the kill process (15).

Photodynamic inactivation of bacteria is considered as one of the promising approaches to overcome the problem of drug resistance. There is also a potential future application with the technology in terms of treating cancer by oxidizing cancerous cells. The technology is being developed in both gel and spray form.

Summary

The hunt for new antimicrobials is of paramount importance. There are signs of a new generation of candidate antimicrobials emerging over the next few years; however, there is more to be done and the antimicrobials at a more advanced stage will not be sufficient to prevent the significant threat to human health posed from multi-drug resistant organisms. For this, more funding is required from governments and greater collaboration between governments, academia and the pharmaceutical sector is necessary.

Other measures which need to be developed are easily available, effective, rapid, and standardized diagnostic tests should be available in order to carry out susceptibility testing and harmonized, global standards for measuring, evaluating, and interpreting data on antimicrobial use and resistance. Furthermore, antimicrobials should be used in moderation by medical personnel. This important aspect of antimicrobial stewardship should include a commitment to use medically important antimicrobial drugs only when necessary to treat, control, and, in some cases, prevent, disease.

References

1. Sandle, T. (2016) Antibiotic / Antimicrobial Resistance. In Boslaugh, S. (Ed.) The Sage Encyclopedia of Pharmacology and Society, Volume 1, Sage Publications: Los Angeles, pp136-139 2. Wi, T., Lahra, M.M., Ndowa, F. et al (2017) Antimicrobial resistance in Neisseria gonorrhoeae: Global surveillance and a call for international collaborative action. PLoS Med 14(7): e1002344 3. CDC. Gonorrhea Statistics, U.S. Centers for Disease Control and Prevention at: https://www.cdc.gov/std/gonorrhea/stats.htm 4. Brown, E. D. & Wright, G. D. (2016) Antibacterial drug discovery in the resistance era. Nature 529, 336–343 5. Newman, D. J. & Cragg, G. M. (2016) Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 79, 629–661 6. Pantel, L., Florin, T., et al (2018) Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site, Molecular Cell, 70 (1): 83-94 7. Hover, B.M., Kim, S-H., Katz, M. et al (2018) Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens, Nature, 3: 415-422 8. Chevrette, M. G. Carlson, C.M, et al (2019) The antimicrobial potential of Streptomyces from insect microbiomes, Nature Communications, 10, Article number: 516 9. Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR. (2018) Omadacycline enters the ring: a new antimicrobial contender. Pharmacotherapy.38(12):1194-1204. doi: 10.1002/phar.2185 10. Sande, T. (2018) The path to next-generation antibiotics. Digital Journal at: http://www.digitaljournal.com/tech-and-science/science/interview-the-path-to-next-generation-antibiotics/article/507056 11. Ghilarov, D. et al (2018) The Origins of Specificity in the Microcin-Processing Protease TldD/E, Structure, 25 (10): 1549-1561 12. Associated Press (2018) HP Delivers Innovations to Public Health with New CDC Pilot Program, at: https://www.apnews.com/db731257c3f4df8878e4dde73262ef42 13. Nass, N.M., Farooque, S., Hind, C. et ai (2017) Revisiting unexploited antibiotics in search of new antibacterial drug candidates: the case of γ-actinorhodin, Scientific Reports 7: 17419

About Author

Dr. Tim Sandle

Dr. Tim Sandle

Dr. Tim Sandle is a pharmaceutical microbiologist, science writer and journalist. Tim Sandle is a chartered biologist and holds a first class honours degree in Applied Biology; a Masters degree in education; and has a doctorate from Keele University.