Bacterial multicellularity as a possible source of antibiotic resistance R. Kras ˇ ovec, I. Jerman Institute Bion, Ljubljana, Slovenia Summary Knowledge about survival of micro-organisms in stressful situations not only influences the evolutionary theory in a fundamental way, but bears an extraordinary importance in finding a global solution to a very concrete urgent problem of mankind, namely bacterial resistance to antibiotics. Recent in vitro experiments demonstrate that the adaptive mutation process involving transient hypermutators could be one of the most important mechanisms whereby bacterial cells achieve the antibiotic resistance. An effective response of the mutation rates to specific selective conditions and an increasing number of conclusive evidence that bacterial cells are indeed communicative and co-operative organisms lead us to a hypothesis that the emergence of the antibiotic resistant mutants through the so-called adaptive mutation is deeply connected with the multicellular organisation of bacterial cells. ª 2003 Elsevier Science Ltd. All rights reserved. INTRODUCTION A problem of acquisition and spreading of antibiotic re- sistance among bacteria has become a major concern in medicine throughout the world. If the problem is not solved quickly and effectively, we may face devastating consequences including the widespread sickness and death from once curable diseases such as tuberculosis. Because of a great impact on mankind, a large number of researchers direct their efforts towards a deeper under- standing of the origin of antibiotic resistance, but the problem is unfortunately still far from being solved on a satisfactory level. There are five known mechanisms whereby bacterial cells achieve their antibiotic resistance: (1) an alteration or a replacement of antibiotic targets; (2) changes of the permeability of the cell membrane, which prevents the antibiotic from entering the cell; (3) an active ex- port of the antibiotic before the drug has a chance to find its intracellular targets; (4) the acquirement of an alternative metabolic pathway that renders the antibi- otic’s target redundant; (5) the production of enzymes that inactivate antibiotics by degrading or chemically modify them (8). These biochemical mechanisms result in resistant cell phenotypes and can be achieved by mutations in intrinsic chromosomal genes or by an acquisition of the external genes. The external resis- tance genes, often called resistance determinants, may be horizontally transferred by plasmids or transposons (8). They are transferred from one organism to another through a cell-to-cell contact through conjugation. Af- ter conjugation both the donor and the recipient pos- sess antibiotic resistance and the recipient itself becomes the donor and can transfer resistance to other recipients. Resistance genes can also enter the cell’s interior via transduction as a part of a bacteriophages’ DNA or they can enter as a naked DNA by transfor- mation. In these two situations the gene will provide an antibiotic resistance only if it is integrated in a stable way by recombination into a plasmid or chro- mosome. Exploring the origins of resistant mutants began at the beginning of the antibiotic era in 1940s, where re- searchers performed classical experiments proving that Medical Hypotheses (2003) 60(4), 484–488 ª 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0306-9877(02)00394-8 484 Received 9 April 2002 Accepted 12 July 2002 Correspondence to: R. Kras ˇ ovec BSc, Institute Bion, Stegne 21, Ljubljana 1000, Slovenia. Phone: +386-1-513-11-47; Fax: +386-1-513-11-46; E-mail: rok.krasovec@bion.si