Mechanism of activity, biosynthesis and identification of beta-lactam antimicrobial drugs

Abstract

Antimikrobni lijekovi su kemoterapeutici koji imaju široku primjenu u humanoj, veterinarskoj i stočarskoj praksi. Beta-laktamski su najraširenija skupina antimikrobnih lijekova koja se zbog vrlo snažnog antimikrobnog djelovanja i vrlo niske toksičnosti najčešće koristi u humanoj i veterinarskoj medicini u liječenju bakterijskih infekcija. Dijele se u skupine penicilina, cefalosporina i monobaktama. Penicilini se dobivaju iz filtrata kulture plijesni Penicillium notatum i Penicillium chrysogenum, a cefalosporini iz filtrata kulture aktinomiceta (Cephalosporium acremonium). Istraživanja su omogućila otkrića aktivne skupine, 6-amino-penicilanske kiseline čijim je izdvajanjem omogućena proizvodnja polusintetskih penicilina koji su nadišli ograničenja prirodnog penicilina G. Fizikalno-kemijska svojstva beta-laktama mogu se mijenjati supstitucijom vodika u karboksilnoj skupini penicilina, odnosno modifikacijom bočnog lanca cefalosporina. Time se povećala otpornost na djelovanje β-laktamaza i proširen spektar djelovanja. Beta-laktami u terapijskim koncentracijama djeluju baktericidno inhibirajući sintezu stanične stijenke bakterija. Penicilini su važni za antibakterijsku kemoterapiju, često u kombinaciji s drugim antimikrobnim lijekovima. Cefalosporini se primjenjuju kao zamjena za peniciline u liječenju infekcija uzrokovanih gram-negativnim bakterijama te u profilaksi pri kirurškim zahvatima. Primjena beta-laktama u životinja koje se koriste kao hrana može dovesti do ostataka tih lijekova u mesu i mesnim prerađevinama, te mlijeku i jajima. Unošenje antimikrobnih lijekova u ljudski organizam hranom, osobito je opasno zbog njihove direktne toksičnosti odnosno kancerogenosti, utjecaja na sastav crijevne mikroflore, mogućih alergijskih reakcija, te pojave otpornosti pojedinih patogenih mikroorganizama, te je njihovo određivanje nužno. Obzirom da se puno koriste u tretmanu mastitisa najčešće su utvrđeni antimikrobni lijekovi u mlijeku. U svrhu određivanja ostataka beta-laktama u hrani životinjskog podrijetla primijenjuju se screening mikrobiološke metode, a identifikacija i kvanifikacija danas se provodi najčešće tekućinskom kromatografijiom tandemskom spektrometrijom masa.Antimicrobal drugs are chemotherapeutics with a wide spectrum of use in human and veterinary medicine and livestock practice. Beta-lactams are the most widespread group of antimicrobal drugs and are most often used in human and veterinary medicine in the treatment of bacterial infections due to their powerful antimicrobial activity and very low toxicity. They are divided into the groups of penicillins, cefalosporins and monobactams. Penicillins are obtained from the filtrate of the mould cultures Penicillium notatum and Penicillium chrysogenum, while cefalosporins are obtained from the filtrate of the actinomycete cultures (Cephalosporium acremonium). Research has lead to the discovery of active groups of 6-amino-penicillin acids, whose isolation has made it possible to produce semi-synthetic penicillins that have surpassed the limitations of natural penicillin G. The physico-chemical properties of the beta-lactams can be altered by substituting hydrogen in the carboxyl group of penicillins, i.e. in modifying the side chain of cefalosporin. This increases the resistance to the activity of β-lactamase and expands the spectrum of activity. Beta-lactams, in therapy concentrations, act as a bacteriocide by inhibiting the synthesis of bacterial cell walls. Penicillins are important for antibacterial chemotherapy, often in combination with other antimicrobal drugs. Cefalosporins are usually used as a replacement for penicillin in treating infections caused by gram-negative bacteria and in prophylaxis for surgery. The use of beta-lactams in animals used for food can result in the residues of these drugs in meat and meat products or milk and eggs. The introduction of antimicrobal drugs in the human body via food is particularly dangerous due to their direct toxicity or carcinogenicity, influences on the composition of the intestinal microflora, possible allergic reactions in sensitive people, and the appearance of resistance of individual pathogenic microorganisms, and therefore their determination is necessary. Considering that they are widely used in the treatment of mastitis, they are the most commonly determined antimicrobal drugs in milk. For the purpose of determining the residues of beta-lactams in food of animal origin, microbiological screening methods are used, and liquid chromatography/tandem mass spectrometry is most often used for identification and quantification