Anti-Infective Drugs: Why Should We Pay Attention?

Abstract

Infectious disease is not a problem of the past; despite significant breakthroughs achieved during the last century in the development of antibiotic drugs, the control of many infectious diseases has not been accomplished. The concern is the problems of rapidly developing drug resistance, re-emerging disease, and the speed of appearance of virulent strains posing global threats. Thus, antibiotic resistance is now a global healthcare threat and today’s armoury of antibiotics is increasingly limited. For some pathogens, the choice from available drugs is now greatly reduced. Increasing mortality from infections caused by resistant strains, and the increasing levels of hospital-acquired infections, together with escalating healthcare costs, have put antibiotic resistance at the top of the healthcare agenda. According to the US Centers for Disease Control and Prevention and studies on deaths attributable to a differing selection of multi-drug resistance (MDR) infections show that, each year, these infections result in an estimated 25,000 deaths in 29 countries in Europe (5.1 per 100,000 inhabitants) and 12,000 deaths in the US (4.0 per 100,000 inhabitants) [1-3]. If all MDR infections and other infections with problematic resistance profiles were included in these studies, the estimate of deaths would be much higher. These figures show that antibiotic resistance has reached a critical point, as human and economic costs escalate. Many pathogens are now completely resistant to beta-lactam antibiotics and MDR resistant Gonorrhoeal strains have emerged [4]. Resistance is a familiar problem in antibiotic therapy, because bacteria have evolved genetic attributes “resistome”, which specifically enable them to withstand antibiotics, which they produce naturally. Killing pathogens is the goal of antibiotic therapy, but there is now a need to extend the capabilities of anti-bacterial therapies, to develop novel anti-infective drugs and strategies that both destroy pathogens and also undermine resistance mechanisms in more effective ways. Prospects and the Needed Rigorous Research Endogenous host defense peptides (HDPs) have retained evolution-tested efficacy against pathogens that have become refractory to traditional antibiotics. Evidence indicates that HDPs target membrane integrity and bioenergetics of microbes that may be less mutable than conventional antibiotic targets [5]. HDPs have, thus, received increasing attention as templates for development of potential anti-infective therapeutics. The HDPs are short cationic amphiphilic peptides with antimicrobial and/or immunomodulatory activities are present in virtually every life form, as an important component of (innate) immune defenses [6]. These HDPs provide a template for two separate classes of antimicrobial drugs. Direct-acting antimicrobial peptides can be rapid-acting and possess an unusually broad spectrum of activity; consequently, they have prospects as new antibiotics, although clinical trials to date have shown efficacy only as topical agents. But for these peptides to fulfill their therapeutic promise and overcome clinical drawbacks, further work is needed to understand their mechanisms of action and reduce the potential for unwanted toxicity, to make them more resistant to protease degradation and improve half-life in serum, as well as to devise means of manufacturing them on a large scale in a consistent and cost-effective manner. In contrast, the role of cationic host-defense peptides in modulating the innate immune response and boosting infection-resolving immunity while dampening potentially