Antibiotic Resistance

By: Ph. Ali Al-Mehanna

 

Antimicrobial resistance is when microorganisms (i.e. bacteria, viruses, fungi, and parasites) become either less susceptible or completely immune to antimicrobial drugs (i.e. antibiotics, antivirals, antifungals, antimalarials, and anthelmintics). New resistance mechanisms are emerging globally, putting us at risk of failing to treat common infectious diseases. As a result, common infections are causing prolonged illness, disability, and death; hence, resistant microorganisms are commonly referred to as “superbugs”.

 
This is going to be the first part of a series of articles exploring antimicrobial resistance; and in this part, we begin by exploring some of the molecular mechanisms of antimicrobial resistance and their relative examples. There are two main factors driving antimicrobial resistance: evolution and clinical/environmental practices. This evolution is aided by poor healthcare practice by health professionals and agricultural use of antibiotics indiscriminately. There are multiple mechanisms by which antimicrobial resistance develops, and they are as follows in no specific order:

 
1) Reduced entry of the antibiotic into the pathogen

Gram negative bacteria have an outer membrane that acts as a permeable barrier preventing large polar molecules from entering the cell. Many antibiotics are small polar entities that are capable of entering the cell through small protein channels called porins. Thus, antimicrobial drug concentrations can be affected markedly depending on the nature of these porins. Therefore, when there is a loss of, absence of, or mutation in a favored porin channel, the drug entry into the cell is slowed or even stopped all together. As such, if the drug requires active transport across the cell membrane, a phenotypic change or mutation that can slow this transport mechanism, can lead to resistance. An example of this mechanism is seen with melarsoprol in the treatment of Trypanosoma brucci disease (also known as Sleeping Sickness). Melarsoprol requires trypanosome P2 protein transporter (porin) to enter through the parasite wall. However, when the parasite either lacks or has a mutant P2 transporter protein, resistance to melarsoprol occurs.

 

2) Resistance due to drug efflux

Efflux pumps on the cytoplasmic membrane of cell walls can expel antibiotics out of the cell as an evolutionary defense mechanism. Microorganisms can be less susceptible to antimicrobics by overexpressing specific efflux pumps, of which there are 5 major types: the multidrug and toxic compound extruder (MATE); the major facilitator superfamily (MFS) transporters; the small multidrug resistant (SMR) system; the resistance nodulation division (RND) exporters; and the ATP binding cassette (ABC) transporters. Antimalarial drugs have faced tragic resistance by the Plasmodium falciparum parasite. A point mutation in the plasmodium flaciparum multidrug resistance gene 1 (Pfmdr1) creates the ABC transporter leading to drug resistance and failure of chemotherapy. Unfortunately, this mechanism of drug resistance is seen with most antimalarial drugs.

 

3) Resistance due to destruction of antibiotic

This is one of the most commonly known mechanisms of antimicrobial resistance. Aminoglycosides and B-lactam are two prominent antibiotics that suffered bacterial resistance by inactivation or destruction. The destruction is seen when strains of bacteria are able to produce aminoglycoside-modifying enzyme and b-lactamase that degrade aminoglycosides and b-lactams, respectively.

 

References

• Hilal-Dandan, R., & Brunton, L. (2013). Goodman and Gilman manual of pharmacology and therapeutics. McGraw Hill Professional.
• Garneau-Tsodikova, S., & Labby, K. J. (2016). Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives. MedChemComm, 7(1), 11-27.
• Kennedy, P. G. (2008). The continuing problem of human African trypanosomiasis (sleeping sickness). Annals of neurology, 64(2), 116-126.
• Ventola, C. L. (2015).The antibiotic resistance crisis: part 1: causes and threats. Pharmacy and Therapeutics, 40(4), 277.