NOVEL ANTIBIOTICS DISCOVERY AND DRUG RESISTANCE REVISITED

NOVEL ANTIBIOTICS DISCOVERY AND DRUG RESISTANCE REVISITED

Kartikeya Tiwari

School of Paramedical and Allied Health Sciences, Al-Karim University (Previously Katihar Medical College), Katihar, Bihar, India.

ABSTRACT: Drug resistance in bacterial strains has often been detected in the last two decades and is increasing yearly. Novel survival mechanisms and over-the-counter antibiotic availability (OTC) complicated this issue, especially in relation to the Asian continent. Resistance to drug/antibiotic is multifactorial viz, plasmid encoding drug resistance, pumping the drug out by pumping mechanism from the bacterial cell, degradation of antibiotic by using enzymes such as β-lactamases, carbapenemase and others. Bacterial drug resistance is a global threat, and the discovery of novel antibiotics to address this challenge has not kept pace. Critical appraisal and drug development timelines in clinical phases made the task costly and tedious. Global pharmaceutical companies have withdrawn their attention, and only a limited number of companies are doing research and development in this field. The present review discusses the current scenario worldwide and introduces one health plan's role in terms of the discovery of novel drugs and increased drug resistance.

Keywords: Carbapenemase, Drug resistant bacterial strains, Enterobacterales, Clostridium difficile, Pseudomonas aeruginosa

INTRODUCTION: Superbugs are drug-resistant pathogenic bacterial strains that cannot be treated with traditional antibiotics due to their unique drug escape mechanisms ^1-2. These emerging drug-resistant bacterial strains are a major threat for humanity. World health organization (WHO) has declared antibacterial resistance or antimicrobial resistance one of the top ten global public health threats facing humanity ^{2, 3}. Now the question arises in each scientist/researcher's mind: how is the drug resistance coming in these bacterial strains? What are the causes behind this? How to address this challenge? Let’s try to figure it out.

Drug Resistance in Bacteria is Multifactorial: Antibiotic resistance comes up naturally, but overuse/misuse of antibiotics in humans, animals and agriculture fastens this process. Many infections are difficult to treat due to the ineffectiveness of antibiotics nowadays. Penicillin discoverer Alexander Fleming (1945) said that the resistance in pathogenic bacterial strains could come up if exposed to low/nonlethal concentrations of drugs.

Industrialization and competition between pharmaceutical industries (research and development unit) to make more profit ended up with large number of antibiotics generation by generation in a comprehensive manner with improper collaboration and tie-ups at global level. Excessive use of chemical pesticides in agriculture, overuse of antibiotics by rural people and availability of over-the-counter (OTC) antibiotics in developing countries leads to complicate the condition. Thus, most of the pathogenic bacterial strains became drug-resistant year by year ^4-8.

The Interplay of Many Factors influences the use of Antimicrobials in Animal and Plant Production: Burden of diseases that are otherwise preventable through modification of environmental hygiene, nutrition, husbandry and other management practices, Limited access to animal and plant health experts, as well as limitations in training and support for these experts. The use of antimicrobials as growth and production promoters in animals, Lack of regulation and oversight of the use of antimicrobial drugs, over-the-counter or internet sales that make antimicrobial drugs readily available on the patient’s doorstep.

Availability and use of substandard and falsified antimicrobials, Lack of awareness regarding good practices, leading to excessive or inappropriate use, anthropological, sociocultural, political and economic factors ⁸ that pose barriers good practices as shown in Fig. 1.

FIG. 1: INTERCONNECTED SUPPLY CHAIN FOR BACTERIAL DRUG RESISTANCE

Drug resistance is seen in almost all bacterial strains/superbugs, including Mycobacterium species. Severe infections include complicated urinary tract infections, hospital and ventilator acquired pneumonia, multidrug resistance tuberculosis, acute bacterial skin and skin structure infections (ABSSSI), multidrug resistance Neisseria gonorrhoeae and Clostridium difficile infections are becoming difficult to treat due to antibiotic resistance ^{9, 10}. The common mechanism of antibiotic resistance in bacterial strains is shown in Fig. 2.

FIG. 2: DIVERSE MECHANISMS OF DRUG RESISTANCE BY MULTIDRUG-RESISTANT BACTERIAL PATHOGENS

Carbapenemase producing carbapenem resistant Enterobacteriaceae/Enterobacterales (CRE) is a threat to public health due to their unique mechanisms of drug resistance and one of the important groups, as shown in Fig. 3. The major mechanisms by which these superbugs become resistant are enzyme production, efflux pumps and porin mutations.

Out of these, enzyme production was the main mechanism seen in these superbugs. The novel groups/strains such as MBL, (New Delhi metallo-β-lactamase), OXA-48 and KPC (K. pneumoniae carbapenemase-producing) were identified and reported plasmid/gene encoded drug resistance time by time and were considered as major public threat worldwide ^11-25.

FIG. 3: MECHANISMS OF CARBAPENEMASE-PRODUCING CARBAPENEM-RESISTANT ENTEROBACTERIACEAE

Novel Drugs: Novel class of antimicrobial agents has a higher potential to sort out drug resistance than the existing class of antibiotics. However, the current industry pipeline shows a marked gap, denoted as a discovery void. If we look into the causes, we will find multiple factors for this situation. The major challenge faced by all multinational big pharma companies is that the process of novel drug development is tedious, complicated, and costly. Moreover, the discovery task of research and development within a timeline until final approval by FDA is cumbersome ^{15, 16}. Due to instability, most novel molecules cannot pass phase II or phase III. Thus, the big pharma companies are in secured and lose interest due to failure and attrition of the novel drug. Perhaps the novel drug discovery demands more patience and innovative/smarter ways to handle and address this problem because there is still plenty of room to discover new antibiotics. A detailed list of new antibiotics discovered in the latest years is shown in Table 1. WHO and CDC brainstormed and decided on a new concept called a one-health approach. These global organizations decided on one health issue. They declared that the one health approach would be sustainable and comprehensive if novel/new molecules were developed with extended-spectrum against these multidrug-resistant bacterial strains ^{1-7, 17-21}.

Since, antibiotic resistance is one of the issues chosen under one health program. Therefore, these global organizations must come out with a concrete plan in this direction and appreciate the efforts of big pharma companies and the challenging tasks for new antibiotic/molecule discovery.

TABLE 1: LIST OF NOVEL ANTIBIOTICS DISCOVERED IN RECENT YEARS AND THEIR PHASES OF CLINICAL DEVELOPMENT

WHO Guidelines and Preventive Measures to Sort out the Problem: World Health Organization (WHO) adopted the global action plan to address the antibiotic resistance problem with five strategic objectives: to improve awareness and understanding of antimicrobial resistance; to strengthen knowledge through surveillance and research; to reduce the incidence of infection; to optimize the use of antimicrobial agents; and develop the economic case for sustainable investment that takes account of the needs of all countries, and increase investment in new medicines, diagnostic tools, vaccines and other interventions ^1-7.

United Nations Food and Agriculture Organization (UNFAO) Policy and Guidelines: UNFAO plays a role in aquatic and terrestrial livestock health and production, crop production, natural resource management and food safety.  An important area for FAO’s work is to identify and address the critical information gaps on the subject. Moreover, FAO is working closely with key partners such as the World Organization for Animal Health (OIE), the World Health Organization (WHO) and others in a global response to the threat of antimicrobial resistance ^1-7.

Director Generals (2018) of FAO, WHO and OIE agreed to strengthen their long-standing partnership with a strong focus on tackling antimicrobial resistance. These three organizations share the responsibilities for coordinating global activities and tackling antimicrobial resistance through a “One Health” approach, which considers animals, humans and ecosystems simultaneously as shown in Fig. 4.

FIG. 4: CDC AND WHO GLOBAL HEALTH PLAN

FIG. 5: TARGETED DRUG DELIVERY BY NANOMEDICINE-BASED DRUGS

Nanomedicine is the Future: The bio-film-forming potential of drug-resistant bacterial strains makes them more difficult to treat. Destruction of bio-film leads to susceptibility of bacterial cells and is an innovative way to treat complicated abdominal infections, as shown in Fig. 5. Various researchers are studying the polymeric nanoparticles to combat severe infections. Results of nano-antibiotic formulations in therapeutics were impressive and probably are the future. Moreover, it has been reported that the chemical-physical properties and bioavailability of antibiotics increases at a nano scale. So, drug penetration and bacterial cell susceptibility are quite high. Latest examples include inhalation formulations of liposomal ciprofloxacin (Phase I, II, and III) and liposomal amikacin formulation for the treatment of complicated Pseudomonas aeruginosa infections (Phase III) in patients with cystic fibrosis ^37-42.

CONCLUSION: The sky is the limit as far as novel drug development research progress is concerned. Shared interest and collaboration at the global level will give more insight and probably facilitate the decision-making process. Novel antibiotic discovery is just the beginning. Nanomedicine and the combined use of antibiotics will be key role players in treating complicated bacterial infections worldwide. One health approach will also provide new hope and makes a difference in moving forward with significant outcomes.

Funding: No external funding was received for this review article.

ACKNOWLEDGEMENT: NIL

CONFLICT OF INTEREST: Not Applicable

REFERENCES:

1. Laxminarayan R, Matsoso P, Pant S, Brower C, Røttingen JA, Klugman K and Davies S: Access to effective antimicrobials: A worldwide challenge. Lancet 2016; 387: 168–175.
2. Fernandes P and Martens E: Antibiotics in late clinical development. Biochemical Pharmacology 2017; 133: 152–163.
3. World Health Organization. Antibacterial Agents in Clinical Development: An Analysis of the Antibacterial Clinical Development Pipeline 2019.
4. World Health Organization. Antibacterial Agents in Preclinical Development: An Open Access Database2019.
5. Sexually Transmitted Disease Surveillance; U.S. Department of Health and Human Services: Atlanta GA USA 2018.
6. US Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States 2019.
7. European Centre for Disease Prevention and Control 2018.
8. Bradford PA, Miller AA, O’Donnell J and Mueller JP: Zoliflodacin: An oral spiropyrimidinetrione antibiotic for the treatment of Neisseria gonorrhoeae. ACS Infectious Diseases 2020; 6: 1332–1345.
9. Kowalska-Krochmal B and Dudek-Wicher R: The Minimum Inhibitory Concentration of Antibiotics: Methods, Interpretation, Clinical Relevance. Pathogens 2021; 10: 165.
10. O’Donnell J, Lawrence K, Vishwanathan K, Hosagrahara V and Mueller PJ: Single-dose pharmacokinetics, excretion, and metabolism of Zoliflodacin, a novel spiropyrimidinetrione antibiotic, in healthy volunteers. Antimicrobial Agents Chemotherapy 2019; 63: 01808.
11. Navalkele DB and Chopra T: Bezlotoxumab: An emerging monoclonal antibody therapy for prevention of recurrent Clostridium difficile Biological Targets Therapy 2018; 12: 11–21.
12. Sheitoyan-Pesant C, Abou Chakra NC, Pepin J, Marcil-Heguy A, Nault V and Valiquette L: Clinical and healthcare burden of multiple recurrences of Clostridium difficile Infection. Clin Infecti Diseases 2016; 62: 574–80.
13. McDonald CL, Gerding DN, Johnson S, Bakken SJ, Carroll CK, Coffin ES, Dubberke ER, Garey WK, Gould VC and Kelly C: Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clinical Infectious Diseases 2018; 66: 987–994.
14. Cho CJ, Crotty PM and Pardo J: Ridinilazole: A novel antimicrobial for Clostridium difficile Annals of Gastroenterology 2019; 134–140.
15. Achaogen Bankruptcy Raises Worry over Antibiotic Pipeline, CIDRAP–Center for Infectious Disease Research and Policy 2019.
16. Sartelli M, Chichom-Mefire A, Labricciosa MF, Hardcastle T, Abu-Zidan MF, Adesunkanmi KA, Ansaloni L, Bala M, Balogh JZ and Beltrán AM: The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intraabdominal infecions. World Journal of Emerging Surgery 2017; 12: 29.
17. Zhanel GG, Cheung D, Adam H, Zelenitsky S, Golden A, Schweizer F, Gorityala B, Lagacé-Wiens SRP, Walkty A and Gin SA: Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs 2016; 76: 567–588.
18. Snydman RD, McDermott AL, Jacobus VN, Kerstein K, Grossman HT and Sutcliffe AJ: Evaluation of the in-vitro activity of eravacycline against a broad spectrum of recent clinical anaerobic isolates. Antimicrobial Agents Chemotherapy 2018; 62: 02206-02217.
19. Scott JL: Eravacycline: A Review in complicated intra-abdominal infections. Drugs 2019; 79: 315–324.
20. Tulkens MP, Van Bambeke F and Zinner S: Profile of a Novel Anionic Fluoroquinolone-Delafloxacin. Clinical Infectious Diseases 2019; 68: 213–222.
21. Pfaller AM, Sader SH, Rhomberg RP and Flamm KR: In-vitro activity of delafloxacin against contemporary bacterial pathogens from the United States and Europe. Antimicrobial Agents Chemotherapy 2017; 61: 02609-16.
22. Rodenak-Kladniew B, Montoto SS, Sbaraglini M, Di Ianni M, Ruiz M, Talevi A, Alvarez AV, Durán N, Castro RG and Islan AG: Hybrid Ofloxacin/eugenol co-loaded solid lipid nanoparticles with enhanced and targetable antimicrobial properties. International Journal of Pharmacy 2019; 569: 118575.
23. Eleraky EN, Allam A, Hassan BS and Omar MM: Nanomedicine Fight against Antibacterial Resistance: An Overview of the Recent Pharmaceutical Innovations. Pharmaceutics 2020; 12: 142.
24. Terreni M, Taccani M and Pregnolato M: New antibiotics for multidrug-resistant bacterial strains: latest research developments and future perspectives. Molecules 2021; 26(2671): 1-31.
25. Tiwari K: Drug Resistance: Challenges and Updates. J of Natural and Ayurvedic Medicine 2019; 3(3): 1-2.
    

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    How to cite this article:

    Tiwari K: Novel antibiotics discovery and drug resistance revisited. Int J Pharm Sci & Res 2023; 14(9): 4285-91. doi: 10.13040/IJPSR.0975-8232.14(9).4285-91.

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