Why are gram-negative bacteria resistant to antibiotics?
Overview
Bacteria can be divided into two groups on the basis of a process known as crystal violet staining, or Gram staining- these groups are known as gram-positive and gram-negative.
Gram-positive bacteria have a thicker layer of peptidoglycan that makes up the cell wall and thus stain purple in a Gram stain test. Gram-negative bacteria have a cell wall composed of a thin layer of peptidoglycan surrounded by an outer membrane. This outer membrane of gram-negative bacteria contains a unique component, lipopolysaccharide, in addition to proteins and phospholipids.
The outer membrane of gram-negative bacteria is often hidden by a slime layer, which in turn hides the antigens of the cell. The unique structure of the outer membrane of gram-negative bacteria prevents certain drugs and antibiotics from entering into the cell, which means these bacteria have increased resistance to drugs and are more dangerous as disease-causing organisms.
Gram-negative bacteria cause many types of well-known infections. For instance, gram-negative bacteria are responsible for cholera and the bubonic plague. They can also cause respiratory infections, such as certain types of pneumonia. Gonococci bacteria, which cause venereal diseases, and meningococci, which cause bacterial meningitis are also gram-negative.
Antibiotics like vancomycin and other b-lactam antibiotics target peptidoglycan, a substance in the bacteria cell wall. However, these antibiotics are ineffective against gram-negative bacteria because the slime layer in the outer membrane hide the antigens and do not allow these antibiotics to penetrate it.
Gram-negative bacteria have higher levels of transport proteins, which remove toxic substances, such as antibiotics from the cells. Certain gram-negative bacteria can also acquire antibiotic resistance via mutation or acquisition of foreign DNA through gene transfer. One well-known example of this is E. coli, which can cause traveler’s diarrhea and urinary tract infections.
A few antibiotics, such as broad-spectrum penicillins and fluoroquinolones, are currently used to treat infections caused by gram-negative bacteria. In recent years, infections caused by multidrug-resistant gram-negative bacteria have dramatically increased. One treatment for diseases caused by multidrug-resistant gram negative-bacteria is colistin, an organic polymer, but certain bacteria are even developing a resistance to this.
Recently, significant progress has been made in understanding the biogenesis, regulation, and function of bacterial outer membranes. This increased knowledge of the outer membrane may be used to develop new antibiotics to treat resistant gram-negative bacteria. One natural compound that scientists are experimenting with is arylomycin, which can go through the bacterial membrane and bind to the antigens in the cell. Some chemical modifications of this compound have been found to be 500 times more effective than unmodified arylomycin. Experiments with modified arylomycin as an antibiotic to treat gram-negative bacteria have shown some promise in mice; the next exciting phases of testing are in large animals and humans.
Further Reading
Peter A. Smith. Nature (2018) 561,189–194.
J. van der Hejden, et. al. mbio (2016) 7: e01238–16.
Beveridge, T. J. J Bacteriol. (1999) 181, 4725–4733.
J. M. Blair, et. al. Nat Rev Microbiol. (2015) 13, 42–51.
Picture Credit
Atterx Biotherapeutix. http://atterx.com/gn-4474/.
