Circumventing resistance to anti-infective agents

The search for anti-infective agents to treat infections caused by a variety of pathogenic organisms has a long history. Such pathogens include bacteria, viruses, fungi, and diverse higher-order parasites such as protozoa and helminths. The mid-20th century was a period when many remarkable advances were made in the discovery, development and use of anti-infective agents that produced dramatic declines in mortality and morbidity. Of particular note are the low-molecular-weight (MW) compounds that are produced by fermentation processes applied to certain soil-dwelling microbes. Following the discoveries of penicillin and synthetic sulfa drugs, the rapid build-up of the antibiotic armamentarium led to what might be called the Golden Age of antibiotic research during the 1940s – 1970s [1,2]. During this period, most of the major classes of antibiotics in use today were discovered and brought to market. However, by the end of the 20th century, the development and spread of resistance to many previously effective agents had clearly emerged as a severe threat to the future success of antibiotic chemotherapy. This concern was often so severe as to presage the demise of antibiotics and return of medicine to that of a pre-antibiotic era [3-6]. In response to these potentially deleterious outcomes, a most pressing current priority is to identify and develop new antibiotics that will immediately help to treat infections caused by an expanding list of resistant pathogens [7].

However, that challenge represents only half of the overall problem. The long-term solution to resistance is more problematic. The fundamental dilemma is that simply administering a therapeutic dose of an anti-infective substance places selective pressure on pathogens to find ways to block that lethal antibiotic effect and thereby stay alive and grow. This transition from microbial susceptibility to antibiotic resistance can be succinctly summarized in three parts:

Cycle of microbial resistance

1. Create new antibiotics to treat resistant pathogens

2. Pathogens become resistant to new antibiotics

3. Repeat cycle

Medicinal chemists are very skilled for performing item 1 and pathogens are very adept at achieving item 2. However, if the rate of new antibiotic discovery cannot keep pace with the onset of resistance, then we already can foresee that, at some future time, all current antibiotics will eventually lose efficacy. This scenario is partially occurring even now. Breaking this cycle and separating anti-infective activity (high) from resistance development (none) is the ultimate long-term solution. The infectious diseases community needs to be planning for this uncertain future as well as the immediate present [2,8].

Unfortunately, the past decades of traditional antibiotic research have been unsuccessful so far in finding anti-infective low-MW compounds that kill pathogens without eventually eliciting resistance to those agents. Resistance to vancomycin was slow to develop, but even that complex multi-step process eventually occurred. If the present strategies will be insufficient for providing future antibiotics, what will be the alternative mechanistic targets and microbe-modifying agents [9-11]? Antibiotic history thus far indicates that strategies designed to prevent the acquisition, development, or spread of resistance to traditional low-MW antibiotics have not succeeded, at least not on a major scale, and has a discouragingly low probability of succeeding in the future.

One possible solution is to kill pathogens by means other than low-MW antibiotics without fostering resistance. Another suggestion is to use non-lethal means of pathogen control that might not cause resistance to develop. For example, if pathogenicity or virulence were shut down without killing the pathogen, would the pathogen develop resistance to the anti-virulence agent [12,13]? Other examples of different possible non-lethal mechanisms include anti-adhesion materials, sequestration of essential growth nutrients, interference with microbial communication, disruption of colonization, break-up of biofilms, and so on. [2,8,14,15]. This approach has been studied using many different examples of non-lethal agents, but the basic hypothesis still remains to be answered, especially on a large practical scale.

In this issue of EOP, we survey the effects of resistance on several aspects of pharmacotherapy (treatment of diseases in patients by medicines). However, we have not explored other important parts of resistance issues, such as mechanisms of action or resistance in anti-infective substances, which have been well-studied. For this issue, we received 14 contributions divided among a range of pathogenic organisms and diseases, with representatives from bacteria, viruses, fungi, and higher-order parasites. The objective of comparing and contrasting such a widely complex mix of anti-infective compounds and broad range of infectious organisms is to foster discoveries and new insights between different but related fields. We hope that this effort at cross-fertilization will prove to be successful in generating some new ideas.

Finally, I wish to acknowledge the hard work and dedicated efforts of the many authors, reviewers, and Informa Healthcare staff, without whom this special issue would have never been accomplished. Special thanks are bestowed to Amina AbdelLatif and Claire Attwood, the commissioning editors for EOP during this period. Amina was instrumental in initiating the project with me and establishing its early organization and content, whereas Claire brought in the many manuscripts and assembled this issue into a reality. We hope the readers will find the issue to be interesting, stimulating, and potentially useful in developing much-needed new anti-infective materials.