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Does cell culturing contribute to dangerous antibiotic resistance to the same degree as livestock?

Does cell culturing contribute to dangerous antibiotic resistance to the same degree as livestock?


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According to the CDC, antibiotic resistance is one of the biggest public health challenges of our time. The largest incubator for antibiotic resistance is the factory farming of animals where livestock are administered large antibiotic doses often and kept in infection-prone conditions.

Another area where antibiotic use is common is in cell culturing for biological research and engineering. To what degree is this use of antibiotics contribute to the public health challenge today, and moving forward as the biotechnology sector grows?

I am curious both about the impact for yeast cell culturing, and also for the culturing of meats as a future food source. I wonder how the problem differs from the antibiotic resistance problem in the livestock industry, and how this might affect the outlook of a future filled with synthetic biologic products and lab-grown meat.

I see two differences off the bat between livestock farming and cell culturing:

  1. animals have much more powerful immune systems than cultures
  2. culture contamination can be much more readily monitored and responded to by operators

Antibiotics are used in very different ways in cell culture and in livestock farming.

As you note, in farming, antibiotics are used to manage infection in unsanitary conditions and also to increase animal growth. Farming is essentially an inherently non-sterile environment and so there's not really any good way to keep microbes from spreading and interchanging, potentially carrying antibiotics resistance with them.

In cell cultures, on the other hand, one is typically working with a largely sterile environment, and it has to be maintained that way in order for the cell culture to work. They are far, far more delicate than farm animals---but they also can be entirely enclosed in a sealed vessel. Getting a significant contaminant into such an environment is not a "treat the sick animal" situation but a "sterilize and purge the bad batch" situation. Antibiotics are indeed often used as part of this defense, but the potential modes of infection are very different than with animals, which rules out many classes of pathogen simply because they are adapted for respiratory or gastrointestinal transmission, and a cell culture does not have these things.

Moreover, for most current industrial cell cultures, if the product is not the cells themselves, everything alive including pathogens will generally get killed off during later stages of the process (e.g., pasteurization of wine and beer). If the cells themselves are the target of mass-scale culturing, e.g., cultured meat, however, then there will indeed be opportunities for antibiotic resistant pathogens to be developed and spread, particularly as increasing scale of operation offers more opportunities for sloppy operations and regulatory evasion by low-cost operators.

Bottom line: antibiotic resistance is generally far less of a concern with cell culture than with livestock, but may still be at least somewhat of an issue.


What to know about antibiotics

Antibiotics, also known as antibacterials, are medications that destroy or slow down the growth of bacteria.

They include a range of powerful drugs and are used to treat diseases caused by bacteria.

Antibiotics cannot treat viral infections, such as cold, flu, and most coughs.

This article will explain what antibiotics are, how they work, any potential side effects, and antibiotic resistance.


Antibiotics are a common medication that doctors prescribe to fight bacteria.

Antibiotics are powerful medicines that fight certain infections and can save lives when used properly. They either stop bacteria from reproducing or destroy them.

Before bacteria can multiply and cause symptoms, the immune system can typically kill them. White blood cells (WBCs) attack harmful bacteria and, even if symptoms do occur, the immune system can usually cope and fight off the infection.

Sometimes, however, the number of harmful bacteria is excessive, and the immune system cannot fight them all. Antibiotics are useful in this scenario.

The first antibiotic was penicillin. Penicillin-based antibiotics, such as ampicillin, amoxicillin, and penicillin G, are still available to treat a variety of infections and have been around for a long time.

Several types of modern antibiotics are available, and they are usually only available with a prescription in most countries. Topical antibiotics are available in over-the-counter (OTC) creams and ointments.

Some medical professionals have concerns that people are overusing antibiotics. They also believe that this overuse contributes toward the growing number of bacterial infections that are becoming resistant to antibacterial medications.

According to the Centers for Disease Control (CDC), outpatient antibiotic overuse is a particular problem. Antibiotic use appears to be higher in some regions , such as the Southeast.

Use of carbapenems, a major class of last-line antibiotics, increased significantly from 2007 to 2010.

Alexander Fleming, speaking in his Nobel Prize acceptance speech in 1945, said:

“ Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug, make them resistant.”

As the man who discovered the first antibiotic almost 70 years ago predicted, drug resistance is starting to become commonplace.

There are different types of antibiotic, which work in one of two ways:

  • A bactericidal antibiotic, such as penicillin, kills the bacteria. These drugs usually interfere with either the formation of the bacterial cell wall or its cell contents.
  • A bacteriostatic stops bacteria from multiplying.


Antibiotics are ineffective against viruses.

A doctor prescribes antibiotics for the treatment of a bacterial infection. It is not effective against viruses.

Know whether an infection is bacterial or viral helps to effectively treat it.

Viruses cause most upper respiratory tract infections (URTIs), such as the common cold and flu. Antibiotics do not work against these viruses.

If people overuse antibiotics or use them incorrectly, the bacteria might become resistant. This means that the antibiotic becomes less effective against that type of bacterium, as the bacterium has been able to improve its defenses.

A doctor can prescribe a broad-spectrum antibiotic to treat a wide range of infections. A narrow-spectrum antibiotic is only effective against a few types of bacteria.

Some antibiotics attack aerobic bacteria, while others work against anaerobic bacteria. Aerobic bacteria need oxygen and anaerobic bacteria do not.

In some cases, a healthcare professional may provide antibiotics to prevent rather than treat an infection, as might be the case before surgery. This is the ‘prophylactic’ use of antibiotics. People commonly use these antibiotics before bowel and orthopedic surgery.

Antibiotics commonly cause the following side effects:

  • diarrhea
  • nausea
  • vomiting
  • rash
  • upset stomach
  • with certain antibiotics or prolonged use, fungal infections of the mouth, digestive tract, and vagina

Less common side effects of antibiotics include:

  • formation of kidney stones, when taking sulphonamides
  • abnormal blood clotting, when taking some cephalosporins)
  • sensitivity to sunlight, when taking tetracyclines
  • blood disorders, when taking trimethoprim , when taking erythromycin and the aminoglycosides

Some people, especially older adults, may experience bowel inflammation, which can lead to severe, bloody diarrhea.

In less common instances, penicillins, cephalosporins, and erythromycin can also cause inflamed bowels.

Some people may develop an allergic reaction to antibiotics, especially penicillins. Side effects might include a rash, swelling of the tongue and face, and difficulty breathing.

Allergic reactions to antibiotics might be immediate or delayed hypersensitivity reactions.

Anyone who has an allergic reaction to an antibiotic must tell their doctor or pharmacist. Reactions to antibiotics can be serious and sometimes fatal. They are called anaphylactic reactions.

People with reduced liver or kidney function should be cautious when using antibiotics. This may affect the types of antibiotics they can use or the dose they receive.

Likewise, women who are pregnant or breast-feeding should speak with a doctor about the best antibiotics to take.

Individuals taking an antibiotic should not take other medicines or herbal remedies without speaking with a doctor first. Certain OTC medicines might also interact with antibiotics.

Some doctors suggest that antibiotics can reduce the effectiveness of oral contraceptives. However, research does not generally support this.

Nonetheless, people who experience diarrhea and vomiting or are not taking their oral contraceptive during illness because of an upset stomach might find that its effectiveness reduces.

In these circumstances, take additional contraceptive precautions.


People must not stop a course of antibiotics halfway through. If in doubt, they can ask their doctor for advice.

People usually take antibiotics by mouth. However, doctors can administer them by injection or apply them directly to the part of the body with infection.

Most antibiotics start combating infection within a few hours. Complete the whole course of medication to prevent the return of the infection.

Stopping the medication before the course has finished increases the risk that the bacteria will become resistant to future treatments. The ones that survive will have had some exposure to the antibiotic and may consequently develop resistance to it.

An individual needs to complete the course of antibiotic treatment even after they see an improvement in symptoms.

Do not take some antibiotics with certain foods and drinks. Take others on an empty stomach, about an hour before meals, or 2 hours after. Follow the instructions correctly for the medication to be effective. People taking metronidazole should not drink alcohol.

Avoid dairy products when taking tetracyclines, as these might disrupt the absorption of the medication.


Persistence in vitro & in vivo

In vitro or in vivo evidence of chlamydial persistence can be demonstrated in all chlamydia species, and can be routinely induced in the laboratory when infected cells are exposed to β-lactam antibiotics, IFN-γ or are deprived of iron supplements or amino acids [35,36]. Persistent or �rrant’ RBs continue to synthesize proteins and replicate DNA, but they halt cell division. The resulting inclusions contain small numbers of very large aberrant RBs, and yield a prolonged infection caused by viable but nonculturable chlamydia ( Figure 1B & E ). Removal of the stressor results in septum formation, RB division and differentiation to EBs [36]. Failure to respond to antibiotic treatment can follow establishment of chlamydial persistence in vitro, and it may be challenging in vivo to differentiate persistence from potential cases of antibiotic resistance. Although uncomplicated infections are quite responsive to antibiotics, unresolved genital, ocular and respiratory infections that fail to respond to antibiotic treatment are extensively documented [36�]. It is possible that this is a function of poor therapeutic control of aberrant, persistent Chlamydiae in patients.

Both in vitro and in vivo evidence of penicillin treatment show that a dramatic change in the bacterial cell structure can suspend the developmental lifecycle and trigger a persistent state.

Several studies have identified possible ways that antibiotic therapy in clinical settings or long-term infection might lead to phenotypic resistance to antibiotics that are normally very effective in both C. trachomatis and Chlamydia (Chlamydophila) pneumoniae [19,32,39�]. Examples include a study showing that persistent chlamydia became phenotypically resistant to AZM clearance after initial exposure to penicillin [42], and work showing that the macrolide erythromycin blocked EB to RB differentiation if added prior to infection, but caused RBs to enlarge and blocked differentiation to EBs when the antibiotic was added 18 or 24 h postinoculation [43].

The presence of chlamydial RNA and DNA in culture-negative patients showing evidence of chronic chlamydial disease provides support for some form of persistence in clinical settings [44�]. Atypical RBs were found in cases of reactive arthritis (Reiter’s syndrome) and in chronic prostatitis cases caused by C. trachomatis after antibiotic treatment [25,48]. Morphologically aberrant RBs in macrophages from an aortic valve sample from chronic C. pneumoniae infection have been identified [49]. These in vivo reports, along with in vitro experimental data, establish possible mechanisms for clinical treatment failures in chlamydial infections that might lead to erroneous conclusions regarding the antibiotic resistance of a clinical isolate.


Multiplicity of Resistance Mechanisms in Producer Organisms

Most producer organisms contain several mechanisms for self-resistance. For example, S. peucetius relies on DrrAB to efflux doxorubicin (Li et al., 2014 Brown et al., 2017), DrrC to remove the antibiotic from its target DNA (Prija and Prasad, 2017), and DrrD is possibly used to modify the antibiotic to an inactive form (Karuppasamy et al., 2015). In addition, there is also a serine protease capable of sequestering daunorubicin to prevent its re-entry into the cell following efflux (Dubey et al., 2014). Other examples of producers containing several mechanisms for self-resistance include the following: Microbispora ATCC PTA-5024 contains both an efflux pump (MlbJYZ) and a sequestration protein (MlbQ) to protect against NAI-107 (Pozzi et al., 2016) S. rimosus has an ABC multi-drug efflux pump (OtrC) (Yu et al., 2012) and an MFS pump (OtrB) for efflux of oxytetracycline (Mak et al., 2014) along with OtrA to protect the ribosome by antibiotic removal (Doyle et al., 1991) S. fradiae contains several gene products (TlrA, TlrB, and TlrD) that modify the ribosome to prevent tylosin binding and uses TlrC for efflux (Mak et al., 2014) and S. chattanoogensis L10 contains several different efflux pumps for resistance against natamycin (Wang et al., 2017).


How Antibiotic Resistant Bugs Became Resistant To Penicillin, And How Penicillin Could Work Again

Research led by the University of Warwick has uncovered exactly how the bacterium Streptococcus pneumoniae has become resistant to the antibiotic penicillin. The same research could also open up MRSA to attack by penicillin and help create a library of designer antibiotics to use against a range of other dangerous bacteria.

Worldwide Streptococcus pneumoniae causes 5 million fatal pneumonia infections a year in children. In the US it causes 1 million cases a year of pneumococcal pneumonia in the elderly of which up to 7% are fatal. This new research has completely exposed how Streptococcus pneumoniae builds its penicillin immunity and opens up many ways to disrupt that mechanism and restore penicillin as a weapon against these bacteria.

The research was led by Dr Adrian Lloyd of the University of Warwick&rsquos Department of Biological Sciences along with other colleagues from the University of Warwick, the Université Laval, Ste-Foy in Quebec, and The Rockefeller University in New York. The research was funded by Welcome Trust and the MRC.

Penicillin normally acts by preventing the construction of an essential component of the bacterial cell wall: the Peptidoglycan. This component provides a protective mesh around the otherwise fragile bacterial cell, providing the mechanical support and stability required for the integrity and viability of cells of Streptococcus pneumoniae and other bacteria including MRSA.

The researchers targeted a protein called MurM that is essential for clinically observed penicillin resistance and has also been linked to changes in the chemical make up of the peptidoglycan that appear in penicillin resistant Streptococcus pneumoniae isolated from patients with pneumococcal infections.

The researchers found that MurM acted as an enzyme that was key to the formation of particular structures within the S. pneumoniae peptidoglycan called dipeptide bridges that link together strands of the peptidoglycan mesh that contributes to the bacterial cell wall. The presence of high levels of these dipeptide bridges in the peptidoglycan of Streptococcus pneumoniae is a pre-requisite for high level penicillin resistance.

The Warwick team were able to replicate the activity of MurM in a test tube, allowing them to define the chemistry of the MurM reaction in detail and understand every key step of how Streptococcus pneumoniae deploys MurM to gain this resistance.

The results will allow the Warwick team, and any interested pharmaceutical researchers, to target the MurM reaction in Streptococcus pneumoniae in a way which will lead to the development of drugs which will disrupt the resistance of Streptococcus pneumoniae to penicillin.

The same research also offers exciting possibilities to disrupt the antibiotic resistance of MRSA which uses similarly constructed peptide bridges in the construction of the peptidoglycan component of its cell wall. Therefore, thanks to this research, even MRSA could now be opened up to treatment by penicillin.

A further spin-off from this new MurM research, is that the Warwick led researchers are also able to readily reproduce every precursor step the bacterial cell uses to create its peptidoglycan. The tools developed at Warwick open up each step of the creation of the peptidoglycan (MurA, MurB, MurC etc, etc) used by an array of dangerous bacteria. This provides a valuable collection of targets for pharmaceutical companies seeking ways of disrupting antibiotic resistance in such bacteria.

The University of Warwick part of the research team have now established a new network of academics from the fields of chemistry, biology and medicine, as well as pharmaceutical companies to share and exploit this new treasure trove of targets which could help create a range of new designer antibiotic based treatments targeted at a range of bacteria that can cause significant health problems.

This network is the UK Bacterial Cell Wall Biosynthesis Network or UK-BaCWAN and it is supported by the Medical Research Council of the UK.

The full research paper is called Characterization of tRNA-dependent Peptide Bond Formation by MurM in the Synthesis of Streptococcus pneumoniae Peptidoglycan and it has just been published (March 2008) in The Journal of Biological Chemistry, vol 283(10), pages 6402-6417.

Story Source:

Materials provided by University of Warwick. Note: Content may be edited for style and length.


Trends

The absence of a significant overlap of antibiotic-resistant bacteria (ARB) and antibiotic-resistance genes (ARG) between the human microbiome and potential environmental sources should not be interpreted as an indication of risk absence. Hence, screening of ARG pools cannot be used as an accurate measure of the risk for transmission to humans.

The risks of transmission of antibiotic resistance from the environment to humans must be assessed based on ARB (not only on ARG) that are able to colonize and proliferate in the human body. The risk is a function of their fitness in the human body and the presence of resistance and virulence genes.

Even at extremely low abundance in environmental sources, ARB may represent a high risk for human health. The limits of quantification of methods commonly used to screen for ARG in environmental samples may be too high to allow reliable risk assessments.

The past decade has witnessed a burst of study regarding antibiotic resistance in the environment, mainly in areas under anthropogenic influence. Therefore, impacts of the contaminant resistome, that is, those related to human activities, are now recognized. However, a key issue refers to the risk of transmission of resistance to humans, for which a quantitative model is urgently needed. This opinion paper makes an overview of some risk-determinant variables and raises questions regarding research needs. A major conclusion is that the risks of transmission of antibiotic resistance from the environment to humans must be managed under the precautionary principle, because it may be too late to act if we wait until we have concrete risk values.


Summary

The causes of antibiotic resistance are complex and include human behaviour at many levels of society the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.


Why Is Transduction Important?

Transduction can quickly change the genetic makeup of bacterial populations even though they reproduce asexually. This type of gene transfer has the potential for profound effects on bacteria and the habitats they affect.

For example, many strains of bacteria are known to infect and cause disease in humans and other organisms. Antibiotics are a treatment that is usually effective to counter potentially dangerous or even fatal bacterial infections. Some bacterial strains are particularly difficult to eradicate, and require very specific antibiotics.

It is therefore of great concern when bacteria develop resistance to antibiotics – without the use of antibiotics, this could culminate in infections that spread in the body unchecked.

Transduction plays a role in antibiotic resistance. Some bacterial cells have a natural resistance to antibiotics on their cell membranes, making it hard for the antibiotic to bind there. This could be due to a random mutation and would not affect the overall effectiveness of the antibiotic.

However, if a bacteriophage infects an antibiotic-resistant bacterial cell and then transfers that mutated gene to other bacterial cells by transduction, more cells will be antibiotic-resistant, and as they reproduce by binary fission, the number of antibiotic-resistant bacterial cells could increase exponentially.


The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords : antibiotic resistance, gene transfer, health problems, alternative therapies, drug-resistance

Citation: Kumar M, Sarma DK, Shubham S, Kumawat M, Verma V, Nina PB, Devraj JP, Kumar S, Singh B and Tiwari RR (2021) Futuristic Non-antibiotic Therapies to Combat Antibiotic Resistance: A Review. Front. Microbiol. 12:609459. doi: 10.3389/fmicb.2021.609459

Received: 23 September 2020 Accepted: 04 January 2021
Published: 26 January 2021.

Israel Castillo-Juárez, Colegio de Postgraduados (COLPOS), Mexico

José Rivera-Chávez, Universidad Nacional Autónoma de México, Mexico
Miguel Cocotl-Ya༞z, National Autonomous University of Mexico, Mexico

Copyright © 2021 Kumar, Sarma, Shubham, Kumawat, Verma, Nina, Devraj, Kumar, Singh and Tiwari. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


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