Why Do Antibiotics Exist?

Abstract

In the struggle with antibiotic resistance, we are losing. There is now a serious threat of moving into a postantibiotic world. High levels of resistance, in terms of both frequency and strength, have evolved against all clinically approved antibiotics worldwide. The usable life span of new clinically approved antibiotics is typically less than a decade before resistance reaches frequencies so high as to require only guarded usage. However, microbes have produced antibiotics for millennia without resistance becoming an existential issue. If resistance is the inevitable consequence of antibiotic usage, as has been the human experience, why has it not become an issue for microbes as well, especially since resistance genes are as prevalent in nature as the genes responsible for antibiotic production? Here, we ask how antibiotics can exist given the almost ubiquitous presence of resistance genes in the very microbes that have produced and used antibiotics since before humans walked the planet. We find that the context of both production and usage of antibiotics by microbes may be key to understanding how resistance is managed over time, with antibiotic synthesis and resistance existing in a paired relationship, much like a cipher and key, that impacts microbial community assembly. Finally, we put forward the cohesive, ecologically based "secret society" hypothesis to explain the longevity of antibiotics in nature.

Keywords: antibiotic resistance; community assembly; cooperation; evolution.

FIG 1

Antibiotic classes, their clinical introduction, and resistance identification. The resistance-free life spans of the major classes of antibiotics are indicated. Years of first clinical use (indicated by green triangles) reflect approval by regulatory agencies, usually in the United States. In most cases, the discovery of the class of compounds predates clinical approval by several years, although widespread use of the drug would not occur until approvals were secured. The year resistance was first reported in the literature is indicated by a red bar. In cases where resistance was reported prior to clinical approval, the red bar precedes the green triangle, which then points toward the red resistance bar. Cases where clinical approval was received in the same year that resistance was first reported are indicated by a purple circle. The antibiotic class with the longest resistance-free lifetime is polymyxin, which was not commonly used for decades due to toxicity in humans (108).

FIG 2

Effect of antibiotics upon microbial community interactions. In nature, antibiotics can have significant impacts upon interactions between species and strains of microbes. Rather than acting solely as a microbial weapon of warfare, we know that antibiotics can also function as signaling molecules and transcriptional modifiers. Antibiotic compounds can also create opportunities for community mutualisms with strains both resistant and sensitive, depending upon the context of the interaction. This suggests that antibiotics can play important and complex roles in community assembly and diversity and further implies the importance of paired production and resistance genes in microbial ecology.