The biology of Resistance: Multiple Roles for Multidrug Efflux System

One of the most significant challenges facing healthcare today is the bacterial resistance to antibiotic drugs. These serious problems need sustainable solutions, which is why researchers across the globe are working long hours (1). The development of antibiotics treatment is considered one of the major scientific breakthroughs since the 20th century. Before the discovery, the mortality rate from bacterial infection was very high: 40% for streptococcus pneumonia and 80% for staphylococcus aureus (2). It is estimated that most survivors of the World War I had either their legs or arms amputated because of wound infection that could not be treated and spread to other body parts. However, the development of resistant bacterial strains towards antibiotics threatens to reverse the gains of antibiotic treatment. Studies show that the negative impact of bacterial resistance to antibiotics is both economic and clinical. Economic impacts include increased costs of treatment while the clinical impact includes increased mortality rates. The magnitude of these impact increases as the host vulnerability to bacterial infection increases as well as the severity of the disease and strain virulence. One of the reasons for their resistance is the presence an efflux pumps system that prevents the drug from taking effect (1). This paper focuses on the roles, the functions, and the solutions that the medical research can provide. The rationale for the study is that enhanced understanding of the biological circumstances, especially bacterial surrounding the resistance will provide more insight into the further development of strategies that could eliminate bacterial resistance.  

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The Efflux Pumps System

The Efflux pumps system refers to a group of transporters in the body that facilitate the movement of some substances. They are proteins in nature and reside in the cytoplasm membrane of all the cells. The transporters are active and require a lot of chemical energy to function efficiently. Efflux pumps systems are either primary or secondary. The primary sources obtain energy from adenosine triphosphate hydrolysis. On the other hand, symptorters, uniporters and antiporters; all which are secondary active transporters obtain energy from electrochemical potential difference which is generated through injection of sodium  hydrogen ions to or from within the  cell (3, 4). Five main families of the transporters are known, the families are determined by the source of energy that transport them as well as the sequence of the amino acid. The main families/categories include  the ATP-binding cassette super family (ABC),  facilitator super family (MFS), multi antimicrobial extrusion protein family (MATE), small multidrug resistance family (SMR), and the resistance-nodulation-cell division superfamily (RND) (5; 6). The role played by the ATP-binding cassette’s major role is HDL metabolism and cholesterol homeostasis.. It connects and binds the phospholipids and cellular cholesterol to the apolipoproteins that have insufficient lipids. The Major Facilitator Superfamily (MFS) is the largest of all the secondary bacterial efflux transporters. The major role of the MFS is the transportation of substrate in different parts of the body. The MATE transporter has a membrane whose major function is to act as a sodium/drug antiporter. They also function as resistance mediation to a wide variety of dyes, cationic, aminoglycosides, fluroquinolones and other antibodies with diversified structures. They are mainly found in bacteria, eukaryotes, and archaea. The SMR is membrane-embedded transporters used by bacteria to remove antibiotics from the cells. Their small size provides the mechanism by which they offer resistance since they must form dimmers to efflux drugs. The RND are the ones responsible for virulence for gram-negative bacteria (5, 6).

The efflux transporters operate under systems that are vital in the study of medicine. They are essential in the movement of compounds such as antibiotics, toxic substances, and neurotransmitters out of the cells, which makes them necessary for xenobiotic metabolism (7). These systems have been of interest to researchers, as they want to use them to develop inhibitors that can work alongside antibiotics to minimize resistance. They operate through an energy-dependent system that pumps out toxic substances from the body. Some of the pumps are used to resist specific drugs while others challenge multidrug transporters (8).

The efflux pump mechanism is important in resistance of antibiotics because of its linkage to the genetics make up of the bacterial organism. The chromosome encodes the system that is responsible for the resistance mechanism. The link between the genetics of the bacteria and the mechanism for resistance is the reason why natural resistance of the bacteria is common.. The resistance capacity of the bacteria which in intrinsic is the factor that enables efflux pump genes to survive in environments that are hostile, for example, the bacteria can survive despite the antibiotics being in the same environment, the resistance mechanism then enables the bacteria to produce and over-express genes that infer mutation and further resist the antibiotics. Easy transportation of the genes makes it efficient to spread the resistant genes to different parts of the body. Alternatively, the antibiotics have the capacity of regulating or inducing the expression of the resistance bacterial genes, as a result, bacteria with multiple efflux pumps can develop resistance. 

Antibiotics are the most important substrate of efflux systems and have many functions. However, it is possible that they have other physiological uses, for instance, there is an E. Coli ArcAB efflux system helps in pumping bile and fatty acids to lower their toxic levels (10). The second one is the ArcAB-To1C system in E.coli that is suspected to have a role in the transportation of calcium-channel components in the E. coli membrane. Others are ArcAB efflux system, MexXY component of the MexXY-OprM multidrug efflux system, the MtrCDE system, and the MFS family Ptr pumps (11). 

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Antibiotic Resistance

Antibiotics prevent and treat bacterial infections, but bacteria may make their use ineffective. Thus, it becomes more difficult to treat such infections, which leads to extra medical bills, extended stays in hospitals, and increases in mortality rates. Bacterial resistance to antibiotics is a significant problem today (12, 13). Consequently, infections that are quick to treat such as tuberculosis, blood poisoning, pneumonia, and food-borne conditions are becoming difficult to handle and impossible to cure in some cases. The situation can be worse for those that do not seek medical expertise (14, 15). 

In 1976, Juliano and Ling discovered the p-glycoprotein that underpinned that efflux pumps exist in the eukaryotic cells (16). Apart from their resistance to antibiotics, they are also a leading cause of resistance to anticancer medication. Moitra et al. reported that the stem cell that causes cancer use the Adenosine Triphosphate-binding cassette (ATB-Cassette) as the guardians of the stem cells (17). Moitra argues that the stem cells have two properties that make them seek protection from the transporters, the pluripotency, and self-renewal. The pluripotency property allows the cells to produce several similar types of other cells found all over the body. On the other hand, the self-renewal property allows the stem cells to regenerate to sustain their survival. Because of these two properties, the stem cells have to stick together throughout their lifetime hence protection from death or damage is crucial. The common efflux pumps include the monocarboxylate transporters (MCTs), multidrug resistance-associated proteins (MRPs), the Na+ phosphate transporters (NPTSs), and the multiple drug resistance proteins (MDR). These carriers are available in all parts of the body including the intestine, liver, parts of the brain, and the proximal renal tubule among others (18). 

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The Mechanism of Efflux

Experts continue to debate on the mechanism of the efflux pump. The consensus is that all bacteria, both the susceptible and resistant produce the efflux pump gene. The same characteristic applies to both the gram-positive and gram-negative bacteria. Webber and Piddock suggested two mechanisms of efflux pump (19). Firstly, some resistant bacteria over-express certain efflux genes that even when subjected to destruction or elimination mechanisms such as treatment with substrates in antibiotics may not be sufficient enough to destroy or eliminate them. Overexpression of efflux pump gene also confers mutation and subsequent resistance to several other substrates, dyes, and disinfectants. Since most antibiotics are delivered in combination with other substrates, chemicals, or substance to be effective, it becomes ineffective to treat bacterial infections with antibiotics that have a combination of other substrates for which the efflux pump already extrude. The second suggestion argues that although most efflux pump genes can be carried in the plasmids of most bacteria, the majority of these are carried in the chromosomes of the bacteria, which explains the higher chances of survival and expression. The ability of most efflux genes to code for specific or several substrates in an antibiotic further complicates the mechanism of the efflux system. Apart from the ABC family, most of the efflux pump transporters use the proton motive force as the source of energy for exporting substrates from the membrane surface of the bacteria. The ABC family uses the ATP hydrolysis energy source. 

Drugs that can be used together with the antibiotics to prevent the extrusion of antibiotics through the efflux pump system are the main focus of current research. Several drugs have so far been identified by researchers but none has yet been approved for use by the relevant authorities. The inhibitors are currently being used to examine the prevalence of efflux pumps in cells, however, there are limited clinical trials. It is also worth noting that some natural products inhibit bacterial efflux pumps, for example, carotenoids, flavonoids, and alkaloids (Stewart & Costerton 138). There are suggestions that the encoding elements of an individual’s genetics mediate the resistance to toxic substances. Multidrug efflux pumps are difficult to deal with because their genomes have evolved (19). Thus, antibiotics may not be effective because their application is recent. Research in recent years suggests that multidrug resistance (MDR) efflux pumps are essential elements in the development of antibacterial resistance (19).