Antibiotic adjuvants: identification and clinical use

The discovery of penicillin by Alexander Fleming in 1928 changed the course of medicine. Since then, antibiotics have represented virtually the only effective treatment option for bacterial infections. However, their efficacy has been seriously compromised by over-use and misuse of these drugs, which have led to the emergence of bacteria that are resistant to many commonly used antibiotics. Bacteria present three general categories of antibiotic resistance: acquired, intrinsic and adaptive (Alekshun and Levy, 2007). Acquired resistance is the result of mutations in chromosomal genes or the incorporation of new genetic material (plasmids, transposons, integrons, naked DNA) by horizontal gene transfer. It provides selective advantage in the presence of antimicrobial compounds and it is passed on to progeny resulting in the emergence of antibiotic-resistant strains. Bacteria have an extraordinary ability to acquire antibiotic resistance, which is best understood from an evolutionary perspective. Thus, while the use of antibiotics as therapeutics started less than 70 years ago, bacterial resistance mechanisms have co-evolved with natural antimicrobial compounds for billions of years (D’Costa et al., 2011). Bacterial intrinsic resistance to antibiotics is, in contrast to acquired resistance, not related to antibiotic selection but to the specific characteristics of the bacteria. Gram-negative bacteria are for example resistant to many antibiotics due to the presence of a lipopolysaccharide-containing outer membrane with low permeability that functions as an extra barrier preventing the entrance of antibiotics into the cell. Furthermore, many bacteria contain efflux pumps that pump antibiotics out of the cell and thereby decrease their effectiveness. Finally, adaptive resistance involves a temporary increase in the ability of a bacterium to survive an antibiotic, mainly as the result of alterations in gene and/or protein expression triggered by environmental conditions (i.e. stress, nutrient conditions, growth state, subinhibitory levels of the antibiotic) (Poole, 2012). In contrast to intrinsic and acquired resistance mechanisms, which are stable and can be transmitted on to the progeny, adaptive resistance is transient and usually reverts upon the removal of the inducing condition. The combination of these antibiotic resistance mechanisms has led to the emergence of multidrug-resistant pathogens, which are a serious threat for medical care. Among other strategies, the discovery or development of new antibiotic agents had been thought to be a solution to overcome the deficiencies of the existing ones. However, development and marketing approval of new antibiotics have not kept pace with the increasing public health threat of bacterial drug resistance. An alternative to the development of new antibiotics is to find potentiators of the already existing ones, a less expensive alternative to the problem (Ejim et al., 2011; Kalan and Wright, 2011). Potentiators of antibiotic activity are known as antibiotic adjuvants. These compounds are active molecules, preferably with non-antibiotic activity, that in combination with antibiotics enhance the antimicrobial activity of the latter. Combinations of two antibiotics are also considered adjuvants when their effect is synergistic (i.e. the coadministration of the two drugs has a significantly greater effect than that of each antibiotic alone). Antibiotic adjuvants can function either by reversing resistance mechanisms in naturally sensitive pathogens or by sensitizing intrinsic resistant strains. Identification of new molecules that can function as adjuvants is currently an important topic of research. In this context, Taylor and colleagues have recently published a work aimed to identify molecules that potentiate the antimicrobial activity of antibiotics commonly used against Gram-positive bacteria but that have, however, little or no effect on Gramnegative pathogens (Taylor et al., 2012). Using the Gram-negative bacterium Escherichia coli as model in combination with the aminocoumarin antibiotic novobiocin, the authors set up and performed a forward chemical genetic screen with a library of 30 000 small molecules. Three rounds of selection in which molecules that did not enhance novobiocin activity, that had intrinsic antibacterial activity, or that had undesirable secondary *For correspondence. E-mail marian.llamas@eez.csic.es; Tel. (+34) 958181600 ext. 309; Fax (+34) 958129600. Microbial Biotechnology (2013) 6(5), 445–449 doi:10.1111/1751-7915.12044 Funding Information PB acknowledges financial support from the Spanish Ministry of Economy through a Juan de la Cierva postdoctoral-fellowship (JCI-2010-06615), and (MAL through a Ramon&Cajal grant (RYC-2011-08874). bs_bs_banner