Molecular aspects of bacterial resistance to antibiotics

Abstract

Antibiotic resistance is one of the most important medical problems today, which the World Health Organization considers a global threat to public health, because every year there is an increase in the frequency of isolation of antibiotic-resistant microorganisms, especially of opportunistic strains capable of forming biofilms with high resistance to drugs. The emergence and spread of bacterial resistance to antibiotics has not only medical but also social significance: the resistance of bacteria to antibiotics (AB) entails a significant increase in treatment costs and a significant increase in mortality among patients in medical institutions. Therefore, knowledge of the molecular mechanisms of resistance is extremely important for the medical community. Search and integration of scientific data on the emergence of mechanisms of microorganisms resistance to antibacterial drugs. To achieve this goal we used systematic reviews accessed via the electronic search engine PubMed, Clinical Trials. According to the literature, a serious problem for medical institutions are bacteria of the ESKAPE group: Enterococcus faecium et faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. These microorganisms are characterized by resistance to most modern AB and, for the most part, they are characterized by the formation of multifaceted biofilms with low matrix permeability, which, in turn, makes it impossible to carry out effective antibiotic treatment of patients. It is known that the process of biofilm formation is controlled by the Quorum sensing (QS) signaling system, which, in turn, controls the biofilm formation process, the synthesis of toxins and enzymes. The components of QS provide intraspecific, interspecific communication, as well as interaction with the cells of the human body, which ensures the survival of bacteria under the action of AB. Among vancomycin-resistant enterococci belonging to the ESKAPE group, the most clinically significant are the VanA and VanB phenotypes, whose genes are part of the Tn 1546 transposon, which can move from chromosomal DNA to plasmids and be transmitted to sensitive bacteria, even methicillin-resistant S.aureus (MRSA), which leads to the formation of more aggressive strains of MRSA. Resistance to β-lactam AB of members of the family Enterobacterales is associated with the ability of these microorganisms to produce β-lactamases, among the diversity of which  the most important are β-lactamases with extended spectrum of activity (ESBL), which belong to the enzymes of molecular class A.  Thus, 200 TEM-type β-lactamases, 170 CTX-M type β-lactamases and 189 SHV-type β-lactamases have been described to date. High frequency of mutations in β-lactamase genes significantly expands the spectrum of resistance of enterobacteria to cephalosporins of I-IV generations and causes resistance to serine β-lactamase inhibitors. Carbapenemases of classes A (GES, SME, KPC, IMI / NMC-A, SFC), C (ACT-1, DHA-1, CMY-2, CMY-10, ADC68), D (ОХА-11, ОХА-15, ОХА-23, ОХА-48) have no less importance in the development of bacterial resistance, as well as enzymes that are not inhibited by clavulanic acid or tazobactam (AmpC, P99, ACT-1, CMY-2, FOX-1, MIR-1, GC1, CMY-37, OXA-1, OXA-10, OXA-11, OXA-15, OXA-23, OXA-48). Metal-β-lactamases of class B include enzymes that provide resistance to all β-lactams, except aztreonam, as well as to protected penicillins (IMP-1, VIM-1, CcrA, IND-1, CphA, Sfh-1). Today, there are more than a few thousand genetic variants of resistance to β-lactam AB, which are easily transferrred by plasmids in intraspecific, interspecific and intergeneric way. No less important is the formation of bacterial resistance to aminoglycosides due to the presence of aminoglycoside-modifying enzymes capable of acetylation, phospholyration or nucleotidylation of antibiotics of this group, and due to macrolides, resistance to which is caused by bacterial target modifications acquisition. Current research data indicate the rapid development and spread of antibiotic resistance among different groups of microorganisms. Throughout the duration of the "antibiotics era", microorganisms form new and new biochemical mechanisms of AB resistance and easily transmit these properties to other bacteria, which in turn significantly complicates the treatment of bacterial infections. To effectively combat antibiotic resistance, it is necessary to lay the groundwork for studying and obtaining new factual data on the mechanisms of AB resistance formation. The optimal control strategy should be based not only on the development of global programs aimed to prevent the spread of AB resistance, but also on the development and implementation of innovative forms of microbiological research.

Keywords: Antibiotic resistance, biofilm, Quorum Sensing system, β-lactamase, carbapenemase, PCR-RF.