The “Love and Hatred” between Antibiotics and Drug-resistant Bacteria

By Erxiao

November 13-19, 2017 are the World Antibiotic Awareness Week determined by WTO. Antibiotics are essential resources for human health, however, their misuse is accelerating the emergence of bacteria resistant to their action, and deeply threatens the control of infectious diseases.

Misuse of antibiotics is the biggest driver of inundated drug resistance

The misuse of antibiotics worldwide results in the antibiotics’ efficacy to increasingly decline and even lose, namely, the antimicrobial resistance (AMR) phenomenon. AMR is a common phenomenon, and has increasingly become a serious global problem threatening the public health. According to the present AMR occurrence and spread speed, people who die of AMR are estimated to reach 10 million every year and the directly medical losses are estimated to reach USD 100 trillion by 2050. The main mechanisms of antibiotic resistance include: (1) Damaging and inactivating antibiotics by enzymes such as β-lactamase, aminoglycoside modifying enzyme, and chloramphenicol acetyltransferase (CAT); (2) Changing permeability of cell membranes to reduce drug uptake or increase exocytosis to prevent drug accumulation; (3) Reducing protein binding by target modification or gene mutation.

Global antibiotic R&D encounter bottlenecks

WTO warned in 2016 that the world was headed for the post-antibiotic era as AMR became increasingly serious; if the final line of antibiotics became ineffective, then common infections and slight injuries would be deadly. It is extremely urgent to look for AMR solutions.

The key to AMR solution lies in development of new antibiotic drugs, besides reducing the unnecessary antibiotic use. The current development of new antibiotic products is mostly modification of existing products or combined use of existing antibiotics. Bacteria are becoming increasingly "cunning" and evolving and mutating so fast that antibiotic R&D are far behind, research is often halted before there are results, the development risks are high, and so are the development costs, therefore, the biotechnology and pharmaceutical companies willing to develop new antibiotics become less and less, and the drugs approved also become less year by year.

New Antibiotics Approved by FDA and Drugs at Later Clinical Trial Phases in 2017

Drug combination is "king"

Due to the difficulties in developing new antibiotics, and proneness of single drugs to induce bacteria to produce drug resistance, clinically, drug combinations are mostly used to reduce or overcome AMR, strengthen antibiotic activity, and improve antibiotic efficacy, including combination of antibiotics, combination of antibiotics and non-antibiotics, and combination of antibiotics and vaccines, etc.

The combination of antibiotics and statins can be called a major breakthrough in overcoming AMR. Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, and generally used to lower cholesterol. The latest research discovers that there is the "lipid raft" with structure and functions similar to eukaryote on the cell membrane of methicillin-resistant Staphylococcus aureu (MRSA), and the scaffolding protein flotillin on the lipid raft interacts with carotenoid on the cell membrane to form functional membrane microdomains (FMMs) which are rich in cholesterol and sphingolipid, and the synthesis of the said cholesterol and sphingolipid depends on mevalonic acid pathway, via which the lipid lowering function of statins is completed, therefore, such drugs can damage the basic structure of cell functional area and remove bacteria’s resistance to antibiotics. Spanish and German researchers published Membrane microdomain disassembly inhibits MRSA antibiotic resistance on Cell on November 2 regarding bacteria’s "lipid raft" structure and the mechanism of action of combination of statins and antibiotics.

Phagotherapy reemerges, and may become a substitute for antibiotics in the future

Phage is the generic term for viruses that can infect microbes like bacteria and fungi. Phages were used by the Eastern Europe and former Soviet Union to treat bacterial infection early before Fleming discovered that penicillin could kill Shigella. According to clinical research, the phages can target, damage and kill bacteria, and are effective against clinically important bacteria, such as staphylococcus, Klebsiella pneumonia, and pseudomonas; and phages have characteristics like low dose, high safety, and less likeliness of resistance. Compared with antibiotics that are encouraged to be taken as soon as possible after infections, phages, if inoculated too early after infections, may stimulate the body’s immune responses, and be eliminated by the body before proliferation, resulting in failure to reach the therapeutic effect. Therefore, a big difficulty for phage treatment is the determination of the best incubation time. However, according to Western medicine, the phagotherapy will become an effective substitute for antibiotics in the near future as the technology continues to develop.