LC-MS/MS-Based quantitative protein profiling can aid mechanistic studies of antimicrobial peptides

Novel antimicrobial drugs are in urgent need to overcome the continuous growth in the emergence of microbial resistance to current drugs. Antimicrobial peptides, a group of relative short (less than 100 amino acid residues), positively charged and amphiphilic peptides produced by a wide range of organisms as part of their first line of defense, are excellent candidates for the new drugs. Systematic and comprehensive understanding their mechanisms of action was thus urgently required. The microbial proteome adjusts rapidly in response to antimicrobial-agent challenge. These responses are highly specific for the physiological impairment encountered and usually directed at either compensating the loss of a particular function or counteracting the inflicted damage. For this reason, proteomic analysis may aid mechanistic studies of antimicrobial agents such as antimicrobial peptides. This chapter begins with an introduction of antimicrobial peptides, their structure classification, mode of action and potential role as novel antimicrobial-drug candidates are also discussed. A brief introduction of proteomic analysis is then presented, the role of quantitative protein profiling in mechanistic studies of antimicrobial peptides is discussed. Finally the quantitative protein profiling platform established by our lab for aiding the mechanistic studies of antimicrobial peptides will be presented. Few developments in the history of medicine have had such a profound effect upon human life and society as the development of the power to control infections by microbes. In the fight against infectious disease, antimicrobial drugs play a remarkable role. The majority of antimicrobial drugs were discovered in the 1940-1960s. Owing to the improved hygiene measures and the success story of the treatment of pathogenic microbes by antimicrobial drugs, in 1969 the Surgeon General of the United States stated that it was time "to close the book of infectious diseases" [1]. Unfortunately, since the heady optimism of the 1960s we have learned to our cost that microbial pathogens still have the capacity to spring unpleasant surprises on the world. The problem of acquired microbial resistance to drugs, recognized since the very beginning of antimicrobial therapy, has become ever more menacing. To combat multidrug-resistant pathogens, novel antimicrobial drugs are in urgent need. This need can be addressed by i) structural modification of the existing antimicrobial drug class such that it is no longer prone to the inactivation mechanism, ii) a combination of an antimicrobial compound and a compound that inhibits the resistance mechanism, or iii) most preferentially, a new drug class with unprecedented targets or mechanisms.