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- Understanding and overcoming antibiotic resistance
Both host and bacteria have coevolved with time, which may be as long as millions of years. Pathogens have amended virulence to get used to the immune system of the host during this time period. It is therefore believed that resistance and virulence have evolved during different eras. Regardless of evolutionary differences, these processes share common features, and both processes are indispensable for the survival of bacteria under adverse environments.
Antibiotic resistance enables bacteria able to overcome therapeutics and virulence is necessary to fight the host immune system. Although other mechanisms like adaptive or compensatory mutations may play their role, the transfer of MGEs might be the key genetic procedure for distribution and coselection of resistance and virulence genes.
Various mechanisms of antibiotic resistance, including drug efflux with the help of efflux pump, enzymatic modifications of the antibiotic, enzymatic breakdown of the antibiotics, and modification in the target sites. MDR opportunistic pathogens like Acinetobacter baumannii and Pseudomonas aeruginosa may grow in niches with high antibiotic pressure where several other bacteria may not be able to survive and these pathogens may dislocate the host microbiota as well. This is an example of how antibiotic resistance may improve the virulence or pathogenicity of such pathogens and make these bacteria be able to survive in such niches.
Therefore, antibiotic resistance might be considered as a virulence factor, particularly in the case of hospital settings where drug-resistant opportunistic bacteria may cause high morbidity and mortality. In general, bacteria may use two mechanisms for resistance: 1 intrinsic resistance and 2 acquired resistance.
Pseudomonas displays a very good example of intrinsic resistance mechanism, due to the absence of a susceptible target site for a particular antibiotic. Triclosan which is a broad spectrum biocide especially against Gram-positive bacteria and several Gram-negative bacteria as well is incapable of preventing the growth of Pseudomonas.
Initially, it was supposed that active efflux is the reason behind this resistance, but recently the presence of fabI insensitive allele encoding an extra enoylacyl carrier protein reductase enzyme, which is a target site for triclosan, has been reported. The reason behind this is the intrinsic variation in the cytoplasmic membrane composition. In Gram-positive bacteria, vancomycin inhibits peptidoglycan crosslinking by targeting d-Ala-d-Ala peptides while in the case of Gram-negative bacteria, vancomycin cannot pass through the outer membrane.
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Various other mechanisms may also help bacteria to acquire resistance including antibiotic efflux or poor drug penetration resulting in the reduction of the intracellular concentration of antibiotic, modification of the antibiotic target site due to posttranslational target modification or genetic mutation of the target, and inactivation of the antibiotic by modification or hydrolysis.
Control of infection has long been a serious concern of the evolutionary race, regardless of the clinical proof that approaches based on small molecule monotherapy are inadequate in resistance settings. Assessment of various nominees for infection control under developmental process suggests that the focus of research would be on discovery and identification of novels antibiotics. Unfortunately, bio-therapeutics like antibiotics, novel combination remedies, and drug delivery procedures still lag behind the production of novel small molecules that are usually an extension of the present drug classes.
Therefore, instead of combating bacterial evolution, control strategies might serve better by pursuing resistance mechanisms based on genetic inspiration, for example, furanones deployed by red sea algae to disturb the quorum sensing of resistant bacteria. Though the role of biologics in the control of bacterial infection is in its infancy, its potential to combat MDR cannot be overlooked. Small molecules would always have a key role in the control of infection; however, on the basis of biological inspiration the search for an effective drug candidate may possibly be pursued more logistically.
By chance, a vast potential subsists between biologics combinations, molecules based on biological inspiration, and drug delivery tools. This type of approach may be crafted through the combination of conventional antibiotics, novel adjuvants, and viable limited delivery strategies. In contrast to various expensive development models which often fail in trials, advanced bioinformatics to determine effective combination delivery and new targets will possibly bring substantial benefits. Implementation of various methods of antibiotic resistance is very significant, as it has a substantial impact on humans and livestock.
Although the resolutions have been anticipated, with few being thrown to tackle the crisis, to date very little action has been taken toward these solutions.
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In the face of rising antibiotic resistance, the antibiotic efficacy looks increasingly bleak. Epidemiological trends in MDR bacteria must be considered in developing treatment strategies for infection control. Optimistically, constant highlighting of the problem would encourage researchers to adopt novel strategies to control bacterial infection with the following criteria: discovery of novel antibiotics, anticipation and prevention of antibiotic resistance, and protection of host microbiota.
Preeminent approaches that come across with this criterion would help the formation of novel combination strategies together with smart and local delivery tools, for example, directed nanoparticles, liposomes, and infection-responsive polymer-controlled delivery. Alternative approaches to antibiotics that are presently in clinical trials are listed in Table 1.
Various product types as alternatives to antibiotics for the therapeutic management of bacterial infections. The use of nanotechnology is emerging in medicine and it is not astounding to see these technologies being applied for the management of the antibiotic resistance menace.
Nanoparticles can be utilized for the therapeutic management of infections in different ways. They can be coupled with existing antimicrobial agents for enhancement of their physiochemical behavior against drug-resistant microbes. Second, the colloidal forms of zinc, silver, copper, and titanium can itself be used as antimicrobial agents. Although the principal targets of antibiotics include the inhibition or disruption of bacterial cell wall, inhibition of proteins, and nucleic acids synthesis, nanoparticles are reported to affect the respiration system and thereby generation of reactive oxygen species that ultimately leads to bacterial death.
Nanoparticles also target the bacterial cell wall; therefore, for example, silver nanoparticles can be coupled with the relevant antibiotics to enhance their antibacterial action through synergy. Antimicrobial peptides AMPs are emerging antimicrobial agents found in animals, microorganisms, and plants and have a broader spectrum especially active against different bacteria, fungi, and protozoans.
The amphipathic nature of AMPs enables interaction and insertion into the cell wall and cellular membranes of microbes. The global burden of AMR has no signs of receding, rather it piles up the pressure on human and veterinary medicine. Akin to global warming, AMR is an ecological calamity of indefinite magnitude and has no apparent way out.
Until the first decade of the current century, scientists and clinicians were not up-to-the-minute about AMR, whereas resistant bacteria had been identified before the discovery of penicillin. Few countries across the globe reported the control of various resistant pathogens especially MRSA, but reasons behind the decline in the resistance of these microorganisms are disputed.
For example, the apparent success to confine MRSA attained in the US by practicing various schemes of hygiene and screenings has been thrown aside because some supplementary factors like overall national decline in the prevalence of MRSA may be a strong reason of MRSA control. Scientific fraternity must appreciate such arguments because we are still struggling to recognize the main interventions prerequisite for AMR control.
Perhaps, the eradication of AMR is unattainable but its progression may be decelerated. The fallacy about the enormity and peril of AMR mapped the current epidemic.
GARDP and Entasis Therapeutics launch global phase 3 trial of zoliflodacin
Additionally, studies showing the burden of AMR influenced the think tanks to peruse the issue with urgency. Countries that crafted inclusive national plans remain successful in controlling AMR. Furthermore, these require a comprehensive endorsement from the government authorities with ample funds. In developing countries, progress is at a very low pace, although some Asian countries including India, in particular, have taken some courageous steps toward AMR control in recent times, for example, the Chennai declaration.
Understanding and overcoming antibiotic resistance
Diagnostics pose a significant impact in the setting up of AMR because it drives clinicians to use antibiotics imprudently. Diagnostics is a pressing issue especially in developing countries because they still rely on conventional microbiological tools to identify bacteria. These gaps could be bridged by developing personalized medicine established based on new and efficient molecular diagnostic tools that would be very helpful to identify patients who actually need antibiotic therapy. One Health Approach could be a very useful tool to study the human—animal interface and guide researchers to design novel screening tools.
This subject is of unique importance and must be taken up earnestly because the transmission pathway of AMR between all components human, animal, and environment of one health has been established. Unwise and irrational use of antibiotics is also a salient factor associated with AMR especially in low and middle income countries LMICs.
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Having a dearth of new antibiotics, it is quite difficult to confront this portion of the problem. Data about the impact of AMR on health and economy of developing countries are inadequate. LMICs have a dire situation in terms of clinical outcomes of many fatal bacterial diseases like newborn sepsis, typhoid, etc.
So, the task is not simply to use conventional options but some customized control policies should also be applied; for example, resistant pathogens should be prioritized like MDR M. Up to the tertiary level, WHO recommendations on infection and disease control should be followed. Comprehensive data should be collected by taking all the national stakeholders including government, academia, and industry on board. Additionally, the industry—academia interface should be improved as both academia and industry have made some fundamental mistakes in the past.
First, in the late 20th century, academia and researchers had a mistaken belief about the elimination of infectious diseases and industry-produced antibiotics enormously. Second, although financial incentives in the form of research grants were provided to the academia and pharmaceutical industry, an inadequate proportion was allocated to academia and industries for the generation of sufficient novel classes of antimicrobial agents as compared to the surge of antibiotic resistance.
Use of alternative therapies for the treatment and control of infectious diseases could also be a different and a prolific option to fend off AMR. These therapies include anti-virulence strategies to play with the virulence factors of bacteria , biological therapies use of monoclonal antibodies, insulin, erythropoietin, etc , and vaccines vaccines against MRSA, MDR M.
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We should seek to increase our knowledge regarding the extent of the AMR issue. Comprehensive, unfailing data collection is crucial in AMR control.