The traditional route for identifying early hits in antibiotic research is to target multiplying bacteria. All current antibiotics have been generated this way. Activity of a potential antibiotic in such assays is predictive of an antimicrobial effect in humans (bearing in mind many compounds are not suitable due to undesirable characteristics such as toxicity). The disadvantage of this route is that the numbers of novel classes of non-toxic compounds which kill multiplying bacteria may have been almost exhausted and those that remain, may require substantial effort and expense to bring to market. Furthermore anti-multiplying agents are almost always either inactive or only partially active against non-multiplying or slowly multiplying or persister bacteria, which leads to the need for multiple doses of antibiotics in order to achieve cure of a bacterial infectious disease. This prolongs the duration of therapy and increases the emergence of resistance. Since bacterial resistance reduces the effectiveness of antibiotics, new ones are required at regular intervals, as the old ones lose their potency for most infections. However, the number of new antibiotics which reach the market each year is falling. Whilst at least 15 classes of antibiotics were introduced into the market between 1940 and 1962, only three new classes of antibiotics have been marketed since then. Together with their subsequent analogues, each class loses effectiveness, at least for some species of bacteria such as Gram-negatives, within 50 years after entry into the market. So, if we continue to use existing technologies for the next 50 years, it is unlikely that we will produce enough new classes to prevent the antibiotic era fading away. A fundamentally new route for antibiotic drug discovery is required if the antibiotic era is to continue. Bacterial molecules have been targeted, in order to create new drugs, but this has not produced any new classes of antibiotics which have reached the market. Another potential way to develop new antibacterials is to use bacteriophages. Although this method has been utilized for decades, no marketed bacteriophages are available in Western countries for licensed medicinal purposes.
In a clinical infection, multiplying and non-multiplying bacteria co-exist. Antibiotics kill multiplying bacteria, but they are very inefficient at killing non-multipliers which leads to slow or partial death of the total target population of microbes in an infected tissue. This prolongs the duration of therapy, increases the emergence of resistance and so contributes to the short life span of antibiotics after they reach the market. Targeting non-multiplying bacteria from the onset of an antibiotic development program is a new concept. This paper describes the proof of principle for this concept, which has resulted in the development of the first antibiotic using this approach. The antibiotic, called HT61, is a small quinolone-derived compound with a molecular mass of about 400 Daltons, and is active against non-multiplying bacteria, including methicillin sensitive and resistant, as well as Panton-Valentine leukocidin-carrying Staphylococcus aureus. It also kills mupirocin resistant MRSA. The mechanism of action of the drug is depolarisation of the cell membrane and destruction of the cell wall. The speed of kill is within two hours. In comparison to the conventional antibiotics, HT61 kills non-multiplying cells more effectively, 6 logs versus less than one log for major marketed antibiotics. HT61 kills methicillin sensitive and resistant S. aureus in the murine skin bacterial colonization and infection models. No resistant phenotype was produced during 50 serial cultures over a one year period. The antibiotic caused no adverse affects after application to the skin of minipigs. Targeting non-multiplying bacteria using this method should be able to yield many new classes of antibiotic. These antibiotics may be able to reduce the rate of emergence of resistance, shorten the duration of therapy, and reduce relapse rates.
A New Approach for the Discovery of Antibiotics by Targeting Non-Multiplying Bacteria: A Novel Topical Antibiotic for Staphylococcal Infections. 2010 PLoS ONE 5(7): e11818. doi:10.1371/journal.pone.0011818