Evolutionary Trajectories toward High-Level β-Lactam/β-Lactamase Inhibitor Resistance in the Presence of Multiple β-Lactamases

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Abstract

ABSTRACT

β-Lactam antibiotics are the first choice for the treatment of most bacterial infections. However, the increased prevalence of β-lactamases, in particular extended-spectrum β-lactamases, in pathogenic bacteria has severely limited the possibility of using β-lactam treatments. Combining β-lactam antibiotics with β-lactamase inhibitors can restore treatment efficacy by negating the effect of the β-lactamase and has become increasingly important against infections caused by β-lactamase-producing strains. Not surprisingly, bacteria with resistance to even these combinations have been found in patients. Studies on the development of bacterial resistance to β-lactam/β-lactamase inhibitor combinations have focused mainly on the effects of single, chromosomal or plasmid-borne, β-lactamases. However, clinical isolates often carry more than one β-lactamase in addition to multiple other resistance genes. Here, we investigate how the evolutionary trajectories of the development of resistance to three commonly used β-lactam/β-lactamase inhibitor combinations, ampicillin-sulbactam, piperacillin-tazobactam, and ceftazidime-avibactam, were affected by the presence of three common β-lactamases, TEM-1, CTX-M-15, and OXA-1. First-step resistance was due mainly to extensive gene amplifications of one or several of the β-lactamase genes where the amplification pattern directly depended on the respective drug combination. Amplifications also served as a stepping-stone for high-level resistance in combination with additional mutations that reduced drug influx or mutations in the β-lactamase gene bla _CTX-M-15 . This illustrates that the evolutionary trajectories of resistance to β-lactam/β-lactamase inhibitor combinations are strongly influenced by the frequent and transient nature of gene amplifications and how the presence of multiple β-lactamases shapes the evolution to higher-level resistance.

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Tight regulation, modulation, and high-level expression by vectors containing the arabinose PBAD promoter.

L. Guzman, D Belin, M J Carson … (1995)

We have constructed a series of plasmid vectors (pBAD vectors) containing the PBAD promoter of the araBAD (arabinose) operon and the gene encoding the positive and negative regulator of this promoter, araC. Using the phoA gene and phoA fusions to monitor expression in these vectors, we show that the ratio of induction/repression can be 1,200-fold, compared with 50-fold for PTAC-based vectors. phoA expression can be modulated over a wide range of inducer (arabinose) concentrations and reduced to extremely low levels by the presence of glucose, which represses expression. Also, the kinetics of induction and repression are very rapid and significantly affected by the ara allele in the host strain. Thus, the use of this system which can be efficiently and rapidly turned on and off allows the study of important aspects of bacterial physiology in a very simple manner and without changes of temperature. We have exploited the tight regulation of the PBAD promoter to study the phenotypes of null mutations of essential genes and explored the use of pBAD vectors as an expression system.

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OXA β-lactamases.

Benjamin Evans, Sebastian Amyes (2014)

The OXA β-lactamases were among the earliest β-lactamases detected; however, these molecular class D β-lactamases were originally relatively rare and always plasmid mediated. They had a substrate profile limited to the penicillins, but some became able to confer resistance to cephalosporins. From the 1980s onwards, isolates of Acinetobacter baumannii that were resistant to the carbapenems emerged, manifested by plasmid-encoded β-lactamases (OXA-23, OXA-40, and OXA-58) categorized as OXA enzymes because of their sequence similarity to earlier OXA β-lactamases. It was soon found that every A. baumannii strain possessed a chromosomally encoded OXA β-lactamase (OXA-51-like), some of which could confer resistance to carbapenems when the genetic environment around the gene promoted its expression. Similarly, Acinetobacter species closely related to A. baumannii also possessed their own chromosomally encoded OXA β-lactamases; some could be transferred to A. baumannii, and they formed the basis of transferable carbapenem resistance in this species. In some cases, the carbapenem-resistant OXA β-lactamases (OXA-48) have migrated into the Enterobacteriaceae and are becoming a significant cause of carbapenem resistance. The emergence of OXA enzymes that can confer resistance to carbapenems, particularly in A. baumannii, has transformed these β-lactamases from a minor hindrance into a major problem set to demote the clinical efficacy of the carbapenems.

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Epidemiology of β-Lactamase-Producing Pathogens

Karen Bush, Patricia A Bradford (2020)

β-Lactam antibiotics have been widely used as therapeutic agents for the past 70 years, resulting in emergence of an abundance of β-lactam-inactivating β-lactamases. Although penicillinases in Staphylococcus aureus challenged the initial uses of penicillin, β-lactamases are most important in Gram-negative bacteria, particularly in enteric and nonfermentative pathogens, where collectively they confer resistance to all β-lactam-containing antibiotics. Critical β-lactamases are those enzymes whose genes are encoded on mobile elements that are transferable among species. Major β-lactamase families include plasmid-mediated extended-spectrum β-lactamases (ESBLs), AmpC cephalosporinases, and carbapenemases now appearing globally, with geographic preferences for specific variants. CTX-M enzymes include the most common ESBLs that are prevalent in all areas of the world. In contrast, KPC serine carbapenemases are present more frequently in the Americas, the Mediterranean countries, and China, whereas NDM metallo-β-lactamases are more prevalent in the Indian subcontinent and Eastern Europe. As selective pressure from β-lactam use continues, multiple β-lactamases per organism are increasingly common, including pathogens carrying three different carbapenemase genes. These organisms may be spread throughout health care facilities as well as in the community, warranting close attention to increased infection control measures and stewardship of the β-lactam-containing drugs in an effort to control selection of even more deleterious pathogens.