Designing Safer and Greener Antibiotics
Abstract
:1. Introduction
- (1)
- The effect on the environment due to the synthetic route selected (number of steps, toxicity of reagents, and treatment of waste). i.e., a shorter, cleaner and greener synthesis is preferred.
- (2)
- Inclusion of impact on the environment studies and lifecycle assessment as part of the drug development process. This should preferably avoid the selection of compounds expected to have a major adverse effect on the environment.
- (3)
- A comprehensive evaluation of the toxicity/biodegradation and possible persistence problem of the antibiotic in the environment. This review will focus on the second factor, with the first and third points included for context rather than a review.
2. Antibiotics
3. Penicillin: The First Drug Casualty to Bacterial Resistance
4. Resistance in the Environment
Sampling Site | Log (CFU/g or 100 mL) | ||||||
Total counts | Gram-negative | Gram-positive | Pseudomonads | E. coli | Enterobacter | Enterococci | |
Dairy farm soil | 8.15 | 8.02 | 7.54 | 5.18 | 2.47 | 4.8 | 3.08 |
Dairy farm cow manure | 6.6 | 5.62 | 6.55 | 2.88 | 2.5 | 3.45 | 1.22 |
Dairy canal water | 5.48 | 5.31 | 4.99 | 2.2 | 1.75 | 2.01 | 1.1 |
Residential garden soil | 6.3 | 5.9 | 6.08 | 3.92 | 2.4 | 3.55 | 2.35 |
Lake by hospital | 5.9 | 5.77 | 5.32 | 3.5 | 2.35 | 2.88 | 1.99 |
Public park canal water | 4.7 | 4.6 | 4.05 | 1.8 | 0.8 | 1.27 | 2.01 |
Residential estate lake | 6.51 | 6.48 | 5.32 | 2.1 | 2.02 | 3.5 | 1.04 |
“A variety of antibiotics and their metabolites at sub-inhibitory level concentrations are suspected to expand resistance genes in the environment. However, knowledge is limited on the causal correlation of trace antibiotics or their metabolites with resistance proliferation”.[15]
5. Damage to Ecosystems
6. Drug Development—Benign by Design
7. Green Chemistry Principles
- PreventionIt is better to prevent waste than treating waste after it is produced [22];
- Atom EconomySynthetic methods should be employed so as to maximize incorporation of all reagents used, in the final product [23];
- Less Hazardous Chemical SynthesesWhen possible reagents and synthetic methods less toxic to human health and the environment should be used [24];
- Designing Safer ChemicalsChemicals should be designed, fit for purpose, with minimum toxicity to humans and the environment [25];
- Safer Solvents and AuxiliariesThe use of auxiliary substances such as solvents, drying agents etc. should be reduced when possible [26];
- Design for Energy EfficiencyThe energy required to perform a chemical process should be kept to a minimum, e.g., temperature and pressure conditions of reactions [27];
- Use of Renewable FeedstocksRaw materials should be from a renewable source if possible [28];
- Reduce Derivatives
- CatalysisEmploying catalysts reduces waste and energy requirements and should be used when possible and appropriate, i.e., selectivity [30].
- Design for DegradationSynthetic molecules should be designed to breakdown in the environment after use to avoid chronic build-up effects. Eventual fate in the environment must be considered [31].
- Real-time Analysis for Pollution PreventionReal-time process monitoring to control and prevent the production of potentially hazardous materials should be employed [32].
- Inherently Safer Chemistry for Accident PreventionSafer reagents, procedures and processes should be employed to reduce the change of accidents and exposure of chemicals to the environment and people [33].
8. Green Research Processes
9. Life Cycle Assessment
- (1)
- Goal, Scope and Definition of a Study;
- (2)
- The Life Cycle Inventory—A Comprehensive and Exhaustive Analysis of all Interactions of a Product with the Environment;
- (3)
- Life Cycle Impact Assessment—Analyzing the Data Gathered in Phase 2 to Assess the Overall Impact of the Object of the Study;
- (4)
- Interpretation of Results—Interpreting Consequences of Data Gathered from Phase 2 and 3, Making an Informed Conclusion and Proposing Suggested Courses of Action.
10. ADMET—Absorption, Distribution, Metabolism, Excretion, Toxicity
11. Green Chemistry—Pharmaceutical Successes
“...eliminates the high-pressure hydrogenation, all metals (rhodium and iron), and the wasteful chiral purification step. The benefits of the new process include a 56 percent improvement in productivity with the existing equipment, a 10–13 percent overall increase in yield, and a 19 percent reduction in overall waste generation”.[50]
“...improve the sustainability of the paclitaxel supply, allows year-round harvest, and eliminates solid biomass waste. Compared to the semisynthesis from 10-DAB, the PCF process has no chemical transformations, thereby eliminating six intermediates. During its first five years, the PCF process will eliminate an estimated 71,000 pounds of hazardous chemicals and other materials. In addition, the PCF process eliminates 10 solvents and 6 drying steps, saving a considerable amount of energy. BMS is now manufacturing paclitaxel using only plant cell cultures”.[51]
12. Ionic Liquids (ILs) as Green API’s
13. Toxicity
Organism | Time (h) | IL | |||
---|---|---|---|---|---|
5 | 6 | 7 | 8 | ||
S. aureus (ATCC 6538) | 24, 48 | 500, 1000 | >2000, >2000 | >2000, >2000 | 1000, 1000 |
Methicillin-res.S.a. (HK5996/08) | 24, 48 | 125, 500 | >2000, >2000 | >2000, >2000 | 2000, 2000 |
S. epidermidis (HK6966/08) | 24, 48 | 500, >2000 | 2000, >2000 | 1000, >2000 | 2000, >2000 |
Enterococcus sp. (HK14365/08) | 24, 48 | 2000, >2000 | >2000, >2000 | >2000, >2000 | 2000, 2000 |
E. coli (ATCC 8739) | 24, 48 | >2000, >2000 | >2000, >2000 | >2000, >2000 | >2000, >2000 |
K. pneumoniae (HK11750/08) | 24, 48 | >2000, >2000 | >2000, >2000 | >2000, >2000 | >2000, >2000 |
K. pneumoniae-ESBL (HK14368/08) | 24, 48 | >2000, >2000 | >2000, >2000 | >2000, >2000 | >2000, >2000 |
P. aeruginosa (ATCC 9027) | 24, 48 | >2000, >2000 | >2000, >2000 | >2000, >2000 | >2000, >2000 |
14. Biodegradation
CO2 Headspace Test | % Biodegradation | ||||
---|---|---|---|---|---|
Compound | 0 day | 7 day | 15 day | 21 day | 28 day |
SDS | 0 | 81 | 85 | 90 | 92 |
12 | 0 | 45 | 54 | 56 | 59 |
13 | 0 | 54 | 59 | 59 | 59 |
14 | 0 | 51 | 58 | 61 | 65 |
15 | 0 | 26 | 30 | 29 | 29 |
CO2 Headspace Test | % Biodegradation | ||||
---|---|---|---|---|---|
Compound | 0 day | 6 day | 13 day | 20 day | 28 day |
SDS | 0 | 67 | 91 | 91 | 87 |
6 | 0 | 42 | 65 | 68 | 64 |
CO2 Headspace Test | % Biodegradation | ||||
---|---|---|---|---|---|
Compound | 0 day | 7 day | 15 day | 21 day | 28 day |
SDS | 0 | 78 | 89 | 91 | 94 |
11 | 0 | 16 | 59 | 61 | 61 |
15. Conclusions
Acknowledgments
Conflicts of Interest
References
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Jordan, A.; Gathergood, N. Designing Safer and Greener Antibiotics. Antibiotics 2013, 2, 419-438. https://doi.org/10.3390/antibiotics2030419
Jordan A, Gathergood N. Designing Safer and Greener Antibiotics. Antibiotics. 2013; 2(3):419-438. https://doi.org/10.3390/antibiotics2030419
Chicago/Turabian StyleJordan, Andrew, and Nicholas Gathergood. 2013. "Designing Safer and Greener Antibiotics" Antibiotics 2, no. 3: 419-438. https://doi.org/10.3390/antibiotics2030419