Overcoming Multi-Drug Resistant Microbes

Common and Emerging Drug-Resistant Pathogens

Some of the most notable multi-drug resistant bacteria include Mycobacterium tuberculosis (TB), Methicillin-resistant Staphylococcus aureus (MRSA), and Vancomycin-resistant Enterococcus (VRE); however, bacteria are not the only problematic drug-resistant microbes. There are also concerns about emerging drug-resistant Candida (pathogenic fungi), Human Immunodeficiency Virus (HIV), and Plasmodium falciparum (causes malaria) making international treatment efforts for multi-drug resistant organisms (MDRO’s) a challenging task. [1]

Mechanisms of Resistance

How do microbes develop resistance to antimicrobials that were once effective? When several microbes are repeatedly exposed to an antimicrobial agent, a single entity may develop a mutation that allows itself to survive in the presence of the antimicrobial while the other microbes are eliminated. This single mutated microbe rapidly multiplies and passes on the mutation to progeny that divide at an exponential rate. [2] Irresponsible use of antimicrobials are a major contributor to emerging drug-resistant pathogens. Common mechanisms of resistance are:

  • Efflux pumps - "pump" the antimicrobial compound out of the cell before it can do its work.
  • Enzymes - can destroy or change the antimicrobial, neutralizing it.
  • Changes in the microbe's outer structure prevent the antimicrobial from attaching to its target.
  • Formation of biofilms which surrounded a group or cluster of the same species of microorganism with a "slime" of extracellular DNA, proteins and polysaccharides that can prevent drug penetration. [3]

Overcoming antimicrobial resistance

Overcoming antimicrobial resistance will require two main strategies: curbing the speed of selection for new resistant strains, and the development of novel antimicrobials that circumvent microbe defenses.

Limiting the evolutionary pressure

Vancomycin is a routinely used antibiotic for the first-line treatment in confirmed MRSA infections. While Vancomycin is still largely effective, strains of Vancomycin Intermediate and resistant Staphylococcus aureus (VISA and VRSA) and Vancomycin-resistant Enterococcus (VRE) are alarming developments that have resulted in a more cautious use of Vancomycin. [4] The more often vancomycin is used, the more selective pressure will be put on bacteria that will likely result in more resistant strains. There is also evidence for a mechanism of vancomycin resistance that may confer cross-resistance to, and may affect susceptibility of daptomycin as a second-line therapy to vancomycin [5]. To prevent irresponsible and over-use of antibiotics, many healthcare organizations have started adopting antimicrobial stewardship programs to advocate for conscientious use of all antimicrobials and keep our current, but limited options effective for as long as possible.

Developing new antimicrobials

Establishing resistance to antimicrobial drugs is a normal evolutionary process, and the need for new antimicrobials may very well be never-ending. There are a variety of angles of attack that researchers choose to take when developing novel antimicrobials

  • Natural product research - Ravu et al. found a strain of Bacillus amyloliquefaciens that showed potent activity against MRSA and fractionalized the bacteria into its organic extracts looking for the active ingredient. [6]
  • Some researchers choose to work off of what we already have, designing novel derivatives of existing antimicrobials. Chen et al. synthesized and tested 25 analogues of an existing agricultural insecticide, chlorantraniliprole, in order to find new insecticide alternatives and assess their bioactive targets. [7]
  • Other researchers look at the purified components of antimicrobial complexes. Shrestha et al. developed a novel antifungal called K20 by deriving it from Kanamycin A, a purified component of the antibiotic kanamycin complex. [8]
  • Repurposing existing drugs - Wang et al. found that an antiparasitic drug, antimony potassium tartrate, had promising antitumor activity blocking angiogenesis. [9]
  • High-throughput screening (abbreviated HTP screening or HTS) allows a targeted approach, in which researchers can pick a specific protein unique to a microbe and go through a library of molecules to find prospective inhibitors. Park et al. saw that many antituberculosis drugs were repeatedly targeting the same bacterial processes as TB gained antibiotic resistance, and screened for inhibitors of a different cellular mechanism. [10]
  • Screening has become increasingly more useful as researchers take aim at novel antimicrobial targets, and new screening processes are being developed all the time. Tanaka and Williamson developed a screen for gametocyte activity to test antimalarial drugs. [11]
  • Some drugs work to undo antimicrobial defenses like antibiofilms. Warner, Cheng, Yildiz, and Linington designed a benzo[1,4]oxazine that would inhibit and disperse biofilm, synergistically working with erythromycin and azithromycin to eradicate bacteria.[12]

Keep reading TOKU-E News to see the ways researchers are searching for novel antibiotics to outpace antimicrobial resistance!



[1] Antimicrobial resistance. (2015, April). Retrieved April 28, 2016, from http://www.who.int/mediacentre/factsheets/fs194/en/

[2] Antibiotic Resistance Questions and Answers. (2015, April 17). Retrieved April 28, 2016, from http://www.cdc.gov/getsmart/community/about/antibiotic-resistance-faqs.html

[3] Høiby, N., Bjarnsholt, T., Givskov, M., Molin, S., & Ciofu, O. (2010). Antibiotic resistance of bacterial biofilms. International Journal of Antimicrobial Agents, 35(4), 322-332. Retrieved April 28, 2016, from http://www.sciencedirect.com/science/article/pii/S0924857910000099

[4] Dhand, A., & Sakoulas, G. (2012). Reduced vancomycin susceptibility among clinical Staphylococcus aureus isolates (“the MIC Creep”): implications for therapy. F1000 Medicine Reports4, 4. http://doi.org/10.3410/M4-4

[5] Sakoulas, G., Alder, J., Thauvin-Eliopoulos, C., Moellering, R. C., & Eliopoulos, G. M. (2006). Induction of Daptomycin Heterogeneous Susceptibility in Staphylococcus aureus by Exposure to Vancomycin. Antimicrobial Agents and Chemotherapy50(4), 1581–1585. http://doi.org/10.1128/AAC.50.4.1581-1585.2006

[6] Ravu, R. R., Jacob, M. R., Chen, X., Wang, M., Nasrin, S., Kloepper, J. W., . . . Li, X. (2015). Bacillusin A, an Antibacterial Macrodiolide from Bacillus amyloliquefaciens AP183. J. Nat. Prod. Journal of Natural Products, 78(4), 924-928. http://doi.org/10.1021/np500911k

[7] Chen, Q., Xiong, L., Luo, M., Wang, J., Hu, C., Zhang, X., . . . Sun, D. (2015). Synthesis, Larvicidal Activities and Antifungal Activities of Novel Chlorantraniliprole Derivatives and Their Target in the Ryanodine Receptor. Molecules, 20(3), 3854-3867. http://doi.org/10.3390/molecules20033854

[8] Shrestha, S. K., Chang, C.-W. T., Meissner, N., Oblad, J., Shrestha, J. P., Sorensen, K. N., … Takemoto, J. Y. (2014). Antifungal amphiphilic aminoglycoside K20: bioactivities and mechanism of action. Frontiers in Microbiology5, 671. http://doi.org/10.3389/fmicb.2014.00671

[9] Wang, B., Yu, W., Guo, J., Jiang, X., Lu, W., Liu, M., & Pang, X. (2014). The Antiparasitic Drug, Potassium Antimony Tartrate, Inhibits Tumor Angiogenesis and Tumor Growth in Nonsmall-Cell Lung Cancer. Journal of Pharmacology and Experimental Therapeutics, 352(1), 129-138. http://doi.org/10.1124/jpet.114.218644

[10] Park, B., Awasthi, D., Chowdhury, S. R., Melief, E. H., Kumar, K., Knudson, S. E., … Ojima, I. (2014). Design, Synthesis and Evaluation of Novel 2,5,6-Trisubstituted Benzimidazoles Targeting FtsZ as Antitubercular Agents.Bioorganic & Medicinal Chemistry22(9), 2602–2612. http://doi.org/10.1016/j.bmc.2014.03.035

[11] Tanaka, T. Q., & Williamson, K. C. (2011). A malaria gametocytocidal assay using oxidoreduction indicator, alamarBlue. Molecular and Biochemical Parasitology177(2), 160–163. http://doi.org/10.1016/j.molbiopara.2011.02.005

[12] Warner, C. J., Cheng, A. T., Yildiz, F. H., & Linington, R. G. (2015). Development of benzo[1,4]oxazines as biofilm inhibitors and dispersal agents against Vibrio cholerae. Chem. Commun., 51(7), 1305-1308. http://doi.org/10.1039/c4cc07003h

[13] Namba, T., Kodama, R., Moritomo, S., Hoshino, T., & Mizushima, T. (2015). Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3β-Snail pathway. Cell Death & Disease6(6), e1795–. http://doi.org/10.1038/cddis.2015.172