Bacterial Antibiotic Resistance

Abstract

The mechanisms by which antibiotic resistance of bacteria takes place are discussed in detail. Among the mechanisms that have been recently elucidated are overexpressed efflux pumps that render the bacterium multidrug resistant; downregulation of porins; target modification; quorum sensing; biofilm production and secretion and plasmids that carry antibiotic resistance genes. The mechanisms discussed also include modulation by agents or genetic regulation that may provide improved antibiotic therapies.

Key Concepts:

  • Efflux pumps, porins and plasmid acquisition play an essential role in the development of multidrug resistance by bacteria.

  • Quorum sensing is essential in biofilm formation.

  • Efflux pumps must be essential for bacterial communication (quorum sensing).

  • Quorum sensing must play an important role in the development of resistance and bacterial survival.

  • Inhibition of EP and QS appear to be crucial to inhibit biofilm formation.

Keywords: bacterial resistance; efflux pumps; porins; quorum sensing; biofilms; target modification; plasmids

Figure 1.

Schematic representation of a possible mechanism for RND response under antibiotic stress and effect of environmental conditions on efflux (example of pH). Hydrophilic compounds enter the cell through porins while hydrophobic compounds can diffuse through the lipophilic membrane to the periplasm. At this point, the noxious agent can be recognised by the pump and extruded to the outside environment or diffuse through the inner membrane to the cytoplasm after which it may also be recognised by the pump and extruded. The above example considers that at pH <6.5 PMF is maintained by the pH difference between the outside of the outer membrane and the cytoplasm. Under these conditions, hydronium ions freely flow through porins and ATP equilibrium is reached through its synthesis. When an antibiotic substrate is bound to the transporter, its dissociation from the transporter channel takes place as a consequence of reduced pH and it is subsequently extruded to the environment. At conditions of environmental pH >6.5, the PMF is maintained mainly by the metabolism and the resulting hydrolysis of ATP and consequent translocation of proton ions to the periplasm. The hydronium ions generated by metabolism may pass through the transporter and any bound substrate will be released as a consequence of the reduction of the internal pH of the transporter protein.

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References

Amaral L, Fanning S and Pagès JM (2011) Efflux pumps of gram‐negative bacteria: genetic responses to stress and the modulation of their activity by pH, inhibitors, and phenothiazines. Advances in Enzymology and Related Areas of Molecular Biology 77: 61–108.

Amaral L and Molnar J (2012) Inhibitors of efflux pumps of Gram‐negative bacteria inhibit Quorum Sensing. Open Journal of Pharmacology 3: 2–2

Amaral L, Udwadia ZF and van Soolingen D (2012) A cheap and effective anti‐MDR/XDR/TDR TB drug is already available. Biochemistry and Pharmacology Open Access Journal 1: e137.

Baugh S, Ekanayaka AS, Piddock LJ and Webber MA (2012) Loss of or inhibition of all multidrug resistance efflux pumps of Salmonella enterica serovar Typhimurium results in impaired ability to form a biofilm. Journal of Antimicrobial Chemotheraphy 67(10): 2409–2417.

Gunn JS (2008) The Salmonella PmrAB regulon: lipopolysaccharide modifications, antimicrobial peptide resistance and more. Trends in Microbiology 16: 284–290.

Liao J, Schurr MJ and Sauer K (2013) The MerR‐like regulator BrlR confers biofilm tolerance by activating multidrug efflux pumps in Pseudomonas aeruginosa biofilms. Journal of Bacteriology 195(15): 3352–3363.

Martins A, Iversen C, Rodrigues L et al. (2009) An AcrAB‐mediated multidrug‐resistant phenotype is maintained following restoration of wild‐type activities by efflux pump genes and their regulators. International Journal of Antimicrobial Agents 34: 602–604.

Martins A, Spengler G, Rodrigues L et al. (2009) pH Modulation of efflux pump activity of multidrug resistant Escherichia coli: protection during its passage and eventual colonization of the colon. PLoS One 4(8): e6656.

Nikaido H and Pagès JM (2012) Broad‐specificity efflux pumps and their role in multidrug resistance of Gram‐negative bacteria FEMS Microbiology Reviews 36: 340–363.

Pagès JM, James CE and Winterhalter M (2008) The porin and the permeating antibiotic: a selective diffusion barrier in Gram‐negative bacteria. Nature Reviews in Microbiology 6(12): 893–903.

Soto SM (2013) Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm. Virulence 4(3): 223–229.

Spengler G, Molnár A, Schelz Z et al. (2006) The mechanism of plasmid curing in bacteria. Current Drug Targets 7: 823–841.

Spratt BG (2012) The 2011 Garrod Lecture: from penicillin‐binding proteins to molecular epidemiology. Journal of Antimicrobial Chemotherapy 67: 1578–1588.

Viswanathan VK (2013) Sensing bacteria, without bitterness? Gut Microbes 4: 91–93.

Viveiros M, Dupont M, Rodrigues L et al. (2007) Antibiotic stress, genetic response and altered permeability of E. coli. PLoS One 2(4): e365.

Further Reading

Amaral L, Lee Y, Schwarz U and Lorian V (1986) Penicillin‐binding site on the Escherichia coli cell envelope. Journal of Bacteriology 167: 492–495.

Bolla JM, Alibert‐Franco S, Handzlik J et al. (2011) Strategies for bypassing the membrane barrier in multidrug resistant Gram‐negative bacteria. FEBS Letters 585(11): 1682–1690.

Donlan RM and Costerton JW (2002) Biofilms: survival mechanisms of clinically relevant microorganisms. Clinical Microbiology Reviews 15(2): 167–193.

Høiby N, Bjarnsholt T, Givskov M, Molin S and Ciofu O (2010) Antibiotic resistance of bacterial biofilms. International Journal of Antimicrobial Agents 35(4): 322–332.

Lima TB, Pinto MF, Ribeiro SM et al. (2013) Bacterial resistance mechanism: what proteomics can elucidate. FASEB Journal 27: 1291–1303.

Lorian V (1993) Medical relevance of low concentrations of antibiotics. Journal of Antimicrobial Chemotherapy 31: 137–148.

Martins A, Hunyadi A and Amaral L (2013) Mechanisms of resistance in bacteria: an evolutionary approach. Open Microbiology Journal 7: 53–58.

Master RN, Deane J, Opiela C and Sahm DF (2013) Recent trends in resistance to cell envelope‐active antibacterial agents among key bacterial pathogens. Annals of the New York Academy of Sciences 1277: 1–7.

Nadell CD, Bucci V, Drescher K et al. (2013) Cutting through the complexity of cell collectives. Proceedings of the Royal Society B: Biological Sciences 280: 20122770.

Silhavy TJ, Kahne D and Walker S (2010) The bacterial cell envelope. Cold Spring Harbor Perspectives in Biology 2: a000414.

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How to Cite close
Martins, Ana, Spengler, Gabriella, Molnár, József, and Amaral, Leonard(Feb 2014) Bacterial Antibiotic Resistance. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001993.pub2]