Staphylococcus Aureus: Horizontal Gene Transfer Scaring Antibiotics

Effective policy implementation is a challenging task, especially when taking into account a particular country’s large size and vast bureaucracy, such as those of the United States. One of the many fields that require constant attention is healthcare policy.  Factors like age, social backgrounds, and community settings interact together to create a complex dynamic wave of issues to address. While certain policies have alleviated some concerns, there are others that require attention. One of these areas that require key attention is the rising concern of antibiotic resistance.

Figure 1 (18)

Microorganisms, particularly bacteria, have the ability to learn from the environment at an amazing rate. They employ a method called horizontal gene transfer, HGT. Blessed with a vast gene pool to modify their genomic blueprints, bacteria can strengthen and reinforce existing resistance against threats like antibiotics [1, 7]. This article will delve into the realms that drive the mechanisms of antibiotics and how horizontal gene transfer translates into antibiotic resistance. After understanding the fundamental mechanisms, the next step is to understand how these mechanisms translate in clinical and community settings through a gram-positive bacterium, called Staphylococcus Aureus.

In the realms of horizontal gene transfer, bacteria engage in various mechanisms to achieve antibiotic resistance. One of the modes involves the uptake and expression of foreign RNA/DNA in the form of conjugated plasmids. Functioning independently of chromosomal DNA, plasmids are double-stranded and often appear circular [12]. Though not all plasmids are essential to the organism’s well being, it can carry essential instructions to initiate selective advantages for the microorganism [15]. Additionally, bacteria can replicate these plasmids for sharing with other microorganisms. Such genomic plasmids may allow the bacteria to synthesize an enzyme called beta-lactam that cleaves antibiotics, like penicillin, thus rendering them useless.

The second mode is transduction. Transduction involves the bacterial DNA transferred from one bacterium to another via a virus, i.e. bacteriophage. Even though bacteriophages hunt bacteria, certain bacteriophages may sometimes play a favorable role. They may allow bacteria to gain resistance against certain antibiotics through genetic recombination. Finally, the last method involves cell-to-cell contact where bacteria use their sex pilus to transfer genomic material to another bacteria [7]. It is particularly important to mention that not all bacteria practice all three modes of HGT since it highly depends on their physiologically characteristics and genetic construct.

From an evolutionary standpoint, it is advantageous for bacteria to carry out horizontal gene transfer. While HGT is beneficial to bacteria, the opposite is certainly true for healthcare. The rate at which antibiotic resistance can spread to other similar species is rising, and all of this is done through bacteria cooperative sharing, labeled horizontal gene transfer. Based on the alarming rate of bacteria conferring antibiotic resistance, the hope is to witness new stable but effective antibiotics to combat these newly mutated species. Hence, before we dive into the first pandemic case of S. Aureus and penicillin, the next part focuses on antibiotic mechanisms.

Designed to cripple the activities at the cellular levels, antibiotics work in four different ways. The first method is the inhibition of nucleic acids, the second is the inhibition of protein synthesis, while the third interferes with cell membrane/wall activities, and the final step involves enzyme system interference [11]. It is a beauty to picture all cells containing genomic material comprised of DNA/RNA. These blueprints are essential in the construction of organelles and enzymes and serve as genomic information for the next generation [13]. Biologists have developed a theory, termed the Central Dogma of “molecular biology”, to help explain the interactive roles DNA, RNA, and protein synthesis are all interrelated to each other and all play essential roles in cell vitality and survival. Hence, the nature of antibiotics to target the essential core element of the Central Dogma of “molecular biology” would impede survival. Placing this into perspectives, S. Aureus has to constantly maintain its thick peptidoglycan cell wall in order to prolong survival. Any disruption to the construction of its thick peptidoglycan cell wall would prove lethal to the microorganism. Thus, the final form of interaction involves enzyme regulation. Destroying enzymes crucial to catalyzing certain cellular functions at certain times would make the S. Aureus defenseless, making antibiotics such an effective weapon.

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Fortunately for bacteria, they are equipped with the ability to share genomic information between different species that may allow the organisms to develop ways to circumvent death. Using the same example, the Staphylcoccus Aureus can engage in HGT to acquire immunity against drugs targeting peptidoglycan bonds linking to create the cell wall [14]. When the world first saw the development of penicillin, the drug was the perfect agent to target the formation of cell wall, a necessary agent for defense. The discovery that penicillin rendered the microorganisms defenseless against the immune system was astonishing. The ability for antibiotics to halt an essential process in the bacteria was never understood or thought possible. Despite the antibiotic’s abilities, bacteria were able to develop alternative methods to circumvent penicillin. Research found that bacteria, like the S. Aureus, were able to construct an antibiotic-cleaving enzyme called beta-lactum. Once S. Aureus gained the ability to overt cell death induced by antibiotics, it can construct conjugated plasmids and pass it along to other strains [3].

Immediately, the ability for bacteria to spread the news of an effective method to defeat antibiotics is a rising concern among researchers. All it takes is a single S. Aureus to propagate the resistance blueprint, especially if the likelihood of passing the resistance genome down to its progenies or to its neighbors is highly favored. This constant sharing of genetic information will only create more potent species. HGT is the most common mode of gene acquirement that will eventually lead to alternations in target antibiotic site and increase drug efflux to prevent further damage done to the microorganism [1, 7]. Additionally, HGT serves different functions, such as  “drug modifications, target protection, bypass resistance, replacement of susceptible drug target and acquisition of novel efflux pumps” [7]. Meanwhile, the multipurpose horizontal gene transfer provides a perfect cyclic ecosystem of community sharing among the microorganism world, while it brings both complexity and complications to the medical community and patients, in the form of treatment failure and antibiotic resistance.

After a thorough understanding of the mechanisms, it is important to examine how the lack of knowledge with penicillin and uncontrolled drug distribution in the United States all helped contribute to the rise of antibiotic resistance. Even before Alexander Fleming unveiled penicillin to the world, he had already stumbled upon the concept of antibiotic resistance. His idea arose from the mass commercialization of using antibiotics. He believes that this soon-to-be-dubbed “miracle drug” should sparingly be used in occasions that strictly demanded this drug instead of using it as an all-purpose drug [2]. The lack of proper understanding of how antibiotics work along with unregulated drug distributions all helped to contribute to the eventual downfall of penicillin. Since penicillin was effective against S. Aureus, it immediately became the drug of choice [16]. However, due to the highly unregulated usage of penicillin, by around 1944, S. Aureus was capable of using beta-lactam to destroy penicillin [1].

 

Figure 4 (10)

Upon closer examination of antibiotics distribution in local communities, it is not surprising to uncover that the combination of socioeconomically challenged individuals with inconsistent treatments may contribute to this developing crisis. Individuals contracted with S. Aureus often undergo uncomplicated skin lesions. However, more serious cases of septicaemia (Staph infection) are possible [8]. Penicillin was the choice of drug when patients were diagnosed with Staph infections. Unfortunately, the frequent uses of this drug ultimately rendered this drug useless.

When penicillin became obsolete, the world needed another effective antibiotic on the market. This alternative was methicillin. Upon releasing the drug, immediately, similar practices made with penicillin are witnessed. The lack of antibiotics controls and proper understandings of the antibiotic resistance once again stormed up a heap of problems. Eventually, the lack of drug control led to new strain of resistance that scientists had to coin a new name, methicillin-resistant S. Aureus (MRSA). During this time, what helped worsen the dilemma was that scientists did not completely understand how S. Aureus gained resistance against various antibiotics, although they suspected conjugated plasmids had a role in horizontal gene transfer. HGT allowed susceptible strains to attain the SCCmecA staphylococcal chromosomal cassette, a plasmid that can successfully integrate itself into the chromosome for replication and usage [3, 5, 7, 8]. By obtaining this staphylococcal chromosomal cassette mecA, S. Aureus is able to produce a penicillin binding protein called PBP2a that, when unregulated, will allow this organism to have low binding affinity against beta-lactam antibiotics like penicillin, methicillin, oxacillin [8].

The combination of decreased antibiotic control and a widespread lack of understanding the mechanism aided and strengthened the empowerment of the SCCmecA to develop into variant forms, each with its flavors of potency. Patients coming to the hospitals with different health backgrounds provided MRSA the ability to set up spawning pools. Primarily, two potent forms of MRSA particularly stand out, the hospital and community-associated MRSA.

The more potent form, hospital-associated MRSA, possessed the SCCmecA type I-III, which allows these microorganisms to be “multidrug-resistant and manifest by infecting wounds, ventilator-associated pneumonia, line infections, and other infections” [8]. Counter to its partner, community-associated MRSA has similar plasmid cassette construction but a less potent type (the SCCmecA type IV cassette). However, both forms target different groups of individuals from various backgrounds [2, 19]. Most importantly, however, we would like to understand how these two forms fit into the overall community and healthcare policies.

Originally, hospitals only witnessed HA-MRSA cases in elderly and younger age groups [4,5]. Nonetheless, with MRSA becoming more rampant and immune to various antibiotics, methicillin-resistant S. Aureus are suddenly appearing in communities. Studies indicate that there is a sudden surge in CA-MRSA cases in places like collegiate football [19]. The synergy between increased risk and prolonged exposure in collegiate football players under skin trauma and crowded environments will lead to more sightings of skin and soft tissue infections (SSTIs).  This continuation of CA-MRSA sightings continues to complicate medical treatments since local communities may not have effective treatment methods to deal with increasingly resistive S. Aureus [20].

Comparing the two different forms of MRSA, CA-MRSA is neither as virulent nor as resistive to antibiotics as its cousin strain. In spite of lacking similar resistance, the type IV cassette allows CA-MRSA to secrete a virulent factor Panton-Valentine leukocidin (PVL) that is “capable of causing severe tissue necrosis and leukocyte destruction” [8, 20]. Even though all strains of MRSA are resistant to penicillin and methicillin, almost all MRSA strains elicit similar symptoms. However, due to socioeconomic disparities at the individual and community levels, physicians may often prescribe ineffective treatments, like penicillin to treat bacteria that may carry resistive plasmids. Hence, patients may not be receiving the best form of treatment and, as a result, may cause the bacteria strain to spread and further inflict more damage [4].

Another problematic issue epidemiologists have identified is specific MRSA strains native only to certain regions of the globe. However, with increasing diversity trends and international traveling, MRSA strains can be carried from, for example, Europe to the United States [20]. Even though most MRSA share similar resistive mechanisms to circumvent antibiotics, they may not share the same plasmid cassette constructs [20]. Intermixing different plasmid constructs will not only increase antibiotic resistance possibilities, but will also complicate medical efforts to contain the problems. Thus, antibiotic treatment alternatives must be readily available and cost-effective compared to today’s antibiotics treatment costs.

While researchers have understood the mechanisms behind how HGT functions in S. Aureus the current problem still lies in educating the public and seeking effective alternatives. In term of alternatives, effective treatment options are available. One research conducted in Poland demonstrated it is possible. The research has indicated that using bacteriophages to target bacteria strains, like CA-MRSA, can be an effective alternative. Not only is targeting specific bacteria strains with bacteriophages a cost-effective method, it is also a highly effective technique to ward off antibiotic resistance [9].

Today, the governmental agencies are investing strongly in media and organizations to educate the consumers of excessive use of antibiotics and new strains. Unlike the efforts by the current Center of Disease Control (CDC) to curb influenza infections by yearly vaccination, educating the average consumer on antibiotic resistance on alternatives is challenging. Fundamentally, the processes of horizontal gene transfer would always remain the same, but keeping up with the constant mutations in field of prokaryotes may add another layer of complication. A probable solution involves the governmental agencies collaborating with the current scientific findings to create usable and understandable information that the consumers will comprehend and practice. Successfully incorporating all these elements can educate the public on how excessive antibiotic usages may have severe consequences. The World Health Organization and the CDC along with other major organizations are teaming together to develop effective policies to deal with drug usages, public awareness, and drug distributions. The collaborative efforts are certainly a positive trend to bringing the warfare on antibiotic resistance to a close.

References:

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Tsung Ming Hung is a third-year student at the University of Chicago majoring in Visual Arts with a Pre-Medical curriculum. Join The Triple Helix Online on Facebook and follow us on Twitter.

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  • E K Silbergeld Johns Hopkins

    this is a very nice review but you have unfortunately neglected to discuss the major driver for HGT and the dissemination of antimicrobial resistance at present: the utilization of antimicrobial drugs in animal feeds at subtherapeutic concentrations which has no role in preventing disease and an unproven utility in animal production