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Technology - Antibiotic Resistance

Atul K. Verma, Ph.D.

Antibiotics have helped improve the “quality of life” ever since the accidental discovery of penicillin approximately 70 years ago.  In the decades following this discovery, multiple classes of antibiotics, e.g., beta-lactams (penicillins belong to this class of compounds, cephalosporins), tetracyclines (terramycin, doxycycline), macrolides (erythromycin, azithromycin), aminoglycosides (e.g., gentamycin), and quinolones (e.g., ciprofloxacin) have been developed and widely used to treat various infections in human or animal subjects.  Antibiotics have contributed immensely towards the increase in the average human life expectancy as supported by the fact that the death rates from infectious deseases had dropped from 797 per hundred thousand in 1900 to only 36 per hundred thousand in 1980.

The emergence of antibiotic resistance has become a major public health concern.  Through millions of years of evolution, bacteria have developed very advanced, and often, parallel mechanisms to fight off any external-stress-causing agent (e.g., an antibiotic).  In response to changes in surrounding conditions, bacteria undergo adaptational transformation to render a drug ineffective in treatment against them – thus developing resistance to that drug.  The emergence of antibiotic resistance is unavoidable and can be considered a “side-effect” of antibiotic use.  But, the extent and the rate at which various pathogens are becoming resistant to the existing drugs are alarming, e.g., ca. 92-98% of MRSA (methicillin resistant Staphylococcus aureus), a common hospital-borne bacteria, are now resistant to the first line of antibiotics – tetracycline, erythromycin, and gentamycin. 

Mechanisms of Antibiotic Resistance.  There are several mechanisms by which bacteria can develop resistance to drugs.  Since these drugs have very specific targets within the bacterial cell, even a small change in the structure of either the target (e.g., adaptational change(s) in the shape or the structure of the “active site”) or the drug molecule (e.g., by releasing enzymes that break down the part of the drug that is responsible for its action) gives rise to bacterial-resistance to these drugs.  Another common mechanism involves the use of efflux-pumps (a bacterial version of “sump-pump”) whereby the molecules of the external stress-causing agent (drug) are transported outside of the bacterial cell.  As a result, the concentration of the drug molecule inside the bacterial cell does not stay above toxic threshold concentrations - rendering the antibiotic ineffective.   Once a cell has developed resistance by any of these mechanisms, the genetic information can get incorporated into plasmids and/or genome.   Bacteria can exchange plasmids with neighboring cells and in the process, the genetic-material carrying the resistance-marker, can be picked up by other bacterial cells in the entire bacterial colony. 

Current Approaches to Address Antibiotic Resistance.    The scientific community has been searching for new approaches to circumvent the problem of antibiotic resistance.  Some of these approaches are already in use and others are at various stages of research and development.  For example, the use of appropriate combinations of anti-infectives, use of agents with novel mechanisms of action (e.g., newly discovered oxazolidinones, Zyvox), and modified treatment schedules of existing antibiotics (e.g., longer duration of therapy or increased dosages) are helping to delay the onset of antibiotic resistance in bacteria. 
The use of an “efflux-inhibitor” - a secondary molecule that can bind to the efflux protein – in combination with an established antibiotic drug, will allow the latter to be effective as an antibiotic agent for bacteria with evolved efflux pumps.  
Resistance to beta-lactam drugs (e.g., penicillins), observed in some bacteria, is a consequence of inactivation of the drug by bacterial enzyme, beta-lactamase.  Bacterial infections, that have become resistant to beta-lactams, are treated with a combination of an appropriate beta-lactam and a beta-lactamase-inhibitor (e.g., clavulinic acid).
Structural variations on the existing antibiotics have resulted in new drugs that interact with different target(s) within the bacteria and have circumvented the resistance problem associated with that family of drugs.

New Targets.  The advent of genomics has provided new information towards a better understanding of resistance mechanisms at molecular levels and has resulted in a number of potential new targets for antibiotics.  Some of these potential targets are described here briefly. 
A part of the bacterial defense mechanism, a set of regulatory proteins, named mar proteins (multiple antibacterial resistance; among this family of proteins, marA is the mar-activator), has been the subject of detailed studies at Tufts University and Paratek Pharmaceuticals (Boston, MA).  Within the bacteria, these mar-proteins regulate a number of important genes that control various life-sustaining bacterial functions.   Thus, a chemical-entity that can inhibit the marA transcription factor may potentially be a weapon, either as a stand-alone agent or in combination with an established antibiotic agent, in the arsenal to fight drug-resistance. 

Another similar approach to fight antibacterial resistance is based on the fact that bacteria develop resistance as a result of gene-mutations.  Researchers at Scripps Institute have recently reported that upon exposure to common antibiotics ciprofloxacin and rifampicin, E. coli develops resistance as a consequence of increased protein-induced-mutation rates and not simply due to a chance occurrence (and propagation) of errors during gene replication, as believed earlier.  Interfering with this protein (LexA) prevented the bacteria from developing resistance to either ciprofloxacin or rifampicin, a tactic that may allow discovery of small molecules that can interfere with this pathway.   Both the approaches (small-molecule-inhibitors of marA and those of LexA) are still at early stages and clinical/commercial candidates remain several years away. 

As mentioned earlier, plasmid-mediated mechanisms are a few of several pathways through which, bacteria develop resistance against antibiotics.  When two different plasmids do not co-segregate in the daughter cell, the net result is the elimination of one of the plasmids - a natural phenomenon known as plasmid-incompatibility.  If the plasmids containing the “resistance-markers” can be removed from bacteria, the resistant bacteria can again become sensitive to antibiotics.  Recent work at the University of Illinois has shown that some small-molecules can trigger plasmid-incompatibility, resulting in the re-sensitization of the bacteria to antibiotics (in this case, aminoglycosides).

Combating Antibiotic Resistance Problem as a Consumer.  As end-users we can adhere to some common-sense practices so as to not make the magnitude of the antibiotic-resistance problem even bigger.  Some precautions include making sure that a doctor-prescribed antibiotic is not terminated prematurely before the entire treatment regimen is complete and making sure that those are administered on time, without missing or delaying any doses.  Antibacterial soaps and house-cleaning agents usually leave residues of the antibacterial agent (compounds that can kill or inhibit bacteria, but are unsuitable to be taken internally due to their toxicity, e.g., triclosan) and through frequent and continuous exposure the pathogens may be forced to develop resistance not only to these antibacterials but also to some antibiotics.  Therefore, these should be used only when absolutely necessary.  The standard soaps and detergents (without the added antibacterials), alcohol, hydrogen peroxide, and chlorine bleach are fully capable of reducing the potential problematic pathogens and those should be preferred.

(Atul K. Verma finished his MS from IIT Kanpur and after completing his Ph.D. from University of Illinois at Urbana-Champaign followed by postdoctoral research at Princeton University, he is currently working as a senior scientist at Paratek Pharmaceuticals, located in Boston, in its medicinal chemistry division. He can be reached by email at averma@paratekpharm.com. )

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